International Agency for Research on Cancer Biennial Report 2006-2007: IARC

Biennial Report 2006 - 2007 Biennial Report 2006 - 2007

International Agency for Research on Cancer

International Agency for Research on Cancer International Agency for Research on Cancer Centre International de Recherche sur le Cancer

SC/44/2 GC/50/2

WORLD HEALTH ORGANIZATION

INTERNATIONAL AGENCY FOR RESEARCH ON CANCER

BIENNIAL REPORT 2006-2007

International Agency for Research on Cancer Lyon, France 2007

ISSN 0250-8613 ISBN 978-92-832-1092-4 Printed in France ©International Agency for Research on Cancer, 2007 150 cours Albert-Thomas, 69372 Lyon Cedex 08, France Distributed on behalf of IARC by the Secretariat of the World Health Organization, Geneva, Switzerland

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International Agency for Research on Cancer 2006-2007 iii

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Table of Contents IARC Medals of Honour . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii Director’s Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . viii IARC Scientific Structure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xv Biostatistics and Epidemiology Cluster . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Epidemiology Methods and Support Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Nutrition and Hormones Team . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Data Analysis and Interpretation Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 Descriptive Epidemiology Production Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 Information Technology Services Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 Radiation Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 Epidemiology and Biology Cluster . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 Infections and Cancer Biology Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34 Infections and Cancer Epidemiology Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 Molecular Carcinogenesis Cluster . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 Carcinogen Identification and Evaluation Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 Molecular Carcinogenesis and Biomarkers Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 Epigenetics Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 54 Genetics and Epidemiology Cluster . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 Lifestyle, Environment and Cancer Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 Genetic Epidemiology Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 Genetic Susceptibility Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74 Pathogenesis and Prevention Cluster . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79 Pathology Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80 Screening Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85 Screening Quality Control Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91 IARC Communications Group . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 Education and Training . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 Division of Administration and Finance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 IARC Ethics Review Committee and Institutional Review Board . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 IARC Governing and Scientific Councils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 Meetings and Seminars Organised at IARC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108 Staff Publications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114

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IARC MEDALS OF HONOUR

Roger Sohier Lecture

Richard Doll Lecture

1993 Gérard Orth (Institut Pasteur, Paris) – Papilloma virus and human cancer 1994 Guy Blaudin de Thé (Institut Pasteur, Paris) – Epidémiologie moléculaire des rétrovirus oncogènes 1995 Richard Peto (Oxford University, UK) – Avoidance of premature death 1996 Dirk Bootsma (Erasmus University, Rotterdam, Netherlands) – DNA repair: maintaining nature’s perfection 1997 Luca Cavalli-Sforza (Stanford University, CA, USA) – Gènes, peuples, langues, cultures 1998 Charles Weissmann (University of Zurich, Switzerland) – Biology and transmission of prion diseases 1999 Jan Pontén (Uppsala University, Sweden) – Sunlight and skin cancer: New insights 2000 Richard Klausner (National Cancer Institute, Bethesda, USA) – The war on cancer: Where we are and where research is taking us 2001 Oliver Brüstle (Institut für Neuropathologie, University of Bonn, Germany) – Embryonic stem cells: Basic concepts and therapeutic applications 2002 Jeffrey Koplan (Centers for Disease Control, Atlanta, USA) – Bioterrorism and public health preparedness 2003 Paul Kleihues (Director, IARC) – Poverty, affluence and the global burden of cancer 2004 Umberto Veronesi (European Institute of Oncology, Milan, Italy) – Breast cancer management and care: Current results and future perspectives 2005 David Lane (University of Dundee, UK) – p53 and human cancer: The next 25 years 2006 Georg Klein (Karolinska Institute, Sweden) - Viral contributions to tumorigenesis 2007 Mariano Barbacid (Centro Nacional de Investigaciones Oncológicas, Spain) - Ras genes, Ras oncogenes and cancer

2004 Richard Doll (London, UK) – Fifty years follow-up of British doctors 2005 Brian MacMahon (Needham, MA, USA) – Epidemiology and the causes of breast cancer 2006 Joseph Fraumeni Jr (National Institutes of Health, United States of America) – Genes and the environment in cancer causation: An epidemiologic perspective 2007 Dimitrios Trichopoulos (Harvard School of Public Health, USA) – Breast cancer: Epidemiology and etiology

IARC Lecture 2005

2006 2007

Tadao Kakizoe (National Cancer Centre, Tokyo, Japan) – Bladder cancer: A model of human cancer determined by environmental factors and genetics Ketayun Dinshaw (Tata Memorial Hospital, Mumbai, India) – Cancer Treatment and Control Komen Foundation, USA. Lecture given by LaSalle D. Leffall on behalf of Ambassador Nancy G. Brinker

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Director’s Introduction The staff of the International Agency for Research on Cancer (IARC), and the Agency diaspora, were saddened to hear of the death of Dr Lorenzo Tomatis, the second Director of the IARC and the founder of the IARC Monographs

Programme for Carcinogen Identification and Evaluation. Dr Tomatis was a welcome visitor to the Agency. He had been participating in the planning meetings for the 100th Volume of the Monographs and had

‘My first contact with Lorenzo Tomatis was not as a scientist but as a writer, when in 1965 he published the book “Il Laboratorio”, describing his frustration working in a research and academic environment in Italy that motivated his decision not to go back to his home country but to stay in the USA. This lead to a successful and outstanding career in cancer research, firstly in Chicago and then in Lyon (France). Whilst working in the laboratory of Dr Philippe Shubik in Chicago he became interested in chemical carcinogenesis and in particular he produced the original observation of an increased risk of cancer in mice in the offspring of mothers exposed to chemical carcinogens. During this period his conviction matured that primary prevention of cancer was the underlining theme and the goal for all his future research. This motivation was a determinant in his decision to move to the IARC in Lyon in 1967 to become Chief of the Unit of Chemical Carcinogenesis. In 1982 he became Director of the Agency, succeeding John Higginson, the first Director of the Agency. He foresaw in this newly formed WHO institution a place where he could develop and implement his ideas on cancer prevention. This was a very interesting and exciting time for the Agency, devoted to the development of programmes and recruitment of staff. The overall goal of the Agency was to integrate cancer epidemiology and basic (laboratory) research with the objectives of assessing cancer incidence and their variations world-wide and understanding, with the integration of laboratory science (molecular epidemiology), the aetiopathogenesis of various types of cancers. This approach was very attractive to epidemiologists and laboratory scientists and resulted in the recruitment of staff who were successful in implementing molecular epidemiological studies in parallel with more traditional cancer epidemiological studies and cancer registries. During this time, and later as a Director, he gave priority to the recruitment of high quality staff and was able to implement programmes that were, and still are, recognized by the international scientific cancer community. In addition to the establishment at the Agency of cancer research laboratories therefore, Lorenzo Tomatis was directly responsible for the initiation and implementation of some major

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agreed to prepare a history of the Monograph Programme for this 100th volume. An appreciation of the life of Dr Tomatis has been prepared by his lifelong friend and ex-IARC scientist, Dr Ruggero Montesano.

research projects. One of these, the ‘IARC Monographs on the Evaluation of Carcinogenic Risk to Humans’, begun in the late sixties was, and still is, a major programme of the IARC. It was something he particularly valued and he continued to keep a critical eye on it even after his retirement from the Agency. He was also interested in cancer in developing countries. Under his Directorship two major projects were initiated on the role of viruses in human cancers. One is The Gambia Hepatitis Intervention Study, which aims to assess the efficacy of HBV vaccination in the prevention of chronic liver diseases and the role of other risk factors, namely aflatoxins and HCV infection in hepatocellular carcinoma. The other project concerns epidemiological studies on the role of human papilloma virus in the aetiology of cervical cancer. Another major project initiated under his Directorship was the prospective study on nutrition and cancer involving thousands of individuals from many European countries. Other activities which he supported were cancer epidemiology and cancer registries, and the IARC Fellowship Programme. The initiation and support of these various projects shows the broad interest of Lorenzo Tomatis in cancer research and underlines the importance he always gave to primary cancer prevention as the most effective approach to reduce cancer mortality world-wide. The implementation of these ideas was, and remains, not always easy and he was able to overcome, with great determination, the difficulties encountered among the scientific communities and elsewhere in this respect. Since his first book “Il Laboratorio”, many other successful books (all in Italian) have been published, describing with humour and an acute eye the various personages and situations encountered in his professional and social life.’

Lorenzo Tomatis died on 21st September 2007 in Lyon, France. Our thoughts go to his wife and son, Delia and Paolo. Dr Ruggero Montesano

Director’s Introduction

The four Heads of the IARC Monographs Programme reunited in 2006

Dr Brian MacMahon during his last visit to the Agency

The International Agency for Research on Cancer joins the international cancer community in mourning the passing, on 5 December 2007, of Brian MacMahon, longtime chair of the Department of Epidemiology at Harvard School of Public Health and a giant in the field of cancer epidemiology. In 1960, Dr MacMahon co-authored Epidemiologic Methods. This textbook became Epidemiology: Principles and Methods, recognised for decades as the definitive text in the field. Besides his work in epidemiology in general, Dr MacMahon was known in

Another sad event was the death of Dr Brian MacMahon, who had been one of the original members of the IARC Scientific Council during the 1960’s and had made a significant contribution to the development of the Agency. Dr MacMahon made an outstanding contribution to the development of cancer epidemiology when he was Chairman of the Department of Epidemiology at Harvard School of Public Health in Boston, Massachusetts. Dr MacMahon received the IARC Medal of Honour in 2005 in recognition of his outstanding contribution to cancer epidemiology and the Agency. An appreciation of the life of Dr MacMahon appears on this page. At a personal level, these deaths were particularly sad since I had worked with both. I was on the Faculty of the Department of Epidemiology at Harvard when Brian was Chairman and it was Lorenzo who appointed me to the Agency staff when I left Harvard.

particular for his advances in breast cancer etiology. He was the lead author on a landmark 1970 study that identified an association between breast cancer risk and the age at which a woman first gives birth. These findings provided new insight into the protective mechanisms of pregnancy and stimulated broad reconsideration of the etiology of breast cancer. In addition to his own work in the field, Dr MacMahon built an epidemiology program at Harvard that produced many leaders in academia and government research. He was honoured with awards from the American Cancer Society, the American Public Health Association and the General Motors Cancer Research Foundation, and was elected to the Institute of Medicine in 1973. In addition, he was awarded honorary doctorates from the University of Athens, the State University of New York, and the University of Birmingham, England. Dr MacMahon was one of the members of the IARC Scientific Council at its inception in the mid-1960’s and made a significant contribution to determining the direction which the Agency took. In addition, he was a long-term collaborator with IARC. In 2005, in recognition of his contributions to cancer research and his contribution to the Agency, Dr MacMahon delivered the 2005 Richard Doll lecture, entitled “Epidemiology and the Causes of Breast Cancer”, and was awarded the IARC Medal of Honour. Brian MacMahon died on 5th December 2007. Our thoughts go to his children Mary, Kathleen, Kevin and Michael

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Director’s Introduction

Introduction The International Agency for Research on Cancer was established by a resolution of the 18th World Health Assembly in 1965 with a defined mission to conduct and promote international collaboration in cancer research with the objective of improving health through a reduction in the incidence of and mortality from cancer throughout the world. The IARC Statutes specify the role of the Agency in planning, promoting and conducting research in all phases of the causation, treatment and prevention of cancer; in the collection and dissemination of information on the epidemiology of cancer, on cancer research and on the prevention and causation of cancer throughout the world; studies on the natural history of cancer; and education and training of personnel for research on cancer. The core values which underpin IARC scientific programmes are expressed through its commitment to meet the highest scientific standards; to adhere to the highest standards of international ethical guidelines; and to retain flexibility to be responsive to new scientific opportunities. The Scientific Programme has a focus on prevention and is based on high quality, uniqueness and additional value over and

above what could be achieved in a single national centre. Apart from its internal programme, the IARC infrastructure encourages collaborations between leading cancer research institutes to take place. During the biennium, IARC has had scientific collaborations underway in some 90 countries of the world: the numbers would be larger if Cancer Registry and Course activities are taken into account. In fulfilling the requirements of the Statutes, IARC has developed some unique programmes which are outstanding and are of great scientific value including the IARC Monographs Programme for Carcinogen Identification and Evaluation, the Descriptive Epidemiology Programme, the Infections and Cancer Programme, the Mechanisms of Carcinogenesis programme, the Gambia Hepatitis Intervention Study, the Screening Programme, the Genetic Epidemiology Programme, the Lifestyle and Cancer Programme and the Fellowships and Training Programme. This Report comprises two distinct parts. The first part describes the work and achievements of each Group in the Agency during the biennium 2006-2007. These reports are presented by Cluster. A second part contains selected highlights of some

Figure 1. Countries with active IARC collaborations (coloured in red) x

key findings and publications arising from the work of the IARC during each of the two years of the biennium and, wherever possible, attempts to place these findings in a wider context. Scientific Findings As a research institute, IARC has to ensure that its research and its research output is of a high quality. In 2007, IARC published over 300 articles in scientific journals with an Impact Factor. This was higher than in 2006 and represents a regular growth since the baseline period (2002-2003). Peerreviewed publications were increased by 45% in 2007 compared to 2002-2003 (Figure 2). The Total Impact Factor of these IARC publications again continued to increase and the total for the biennium 2006-2007 was over 50% increased over 2002-2003 (Figure 3). In January 2004, a list of prominent journals was selected as a benchmark for IARC to publish their best work. There has been a substantial increase in publications in these chosen journals in 2004-2007 (Figure 4). This shows a substantial strengthening of the IARC research activity and this is reflected in the success achieved in

Director’s Introduction

Figure 2. IARC Publications in journals with an impact factor

Journal JAMA JNCI Lancet Lancet Oncology Nature Nature Genetics Nature Medicine NEJM Science

2004-2005 1 13 13 9 0 0 1 1 0

2006-2007 1 14 11 11 1 2 0 1 0

Figure 4. IARC Publications in selected, high-quality journals

obtaining competitive research grants from external sources. A determined effort was made in this direction and the results have been quite remarkable (Figure 5). The increased thoroughness of the review process has contributed to this outcome. The majority of the Groups reviewed have scored very highly on “future plans” and this has been reflected again in the obtention of competitive funding. Scientific Highlights The ninth volume of “Cancer Incidence in Five Continents” has been completed and made available on the IARC website. Cancer Incidence in Five Continents is the recognised reference source on the incidence of cancer in populations around the world. The ninth volume has a wider coverage than before presenting data from around the year 2000 not only for entire populations but also for sub-populations living in the same geographic area. This volume presents incidence data from populations all over the world for which good quality data are available. Scanning through the information gives a

Figure 3. Total Impact Factor Score of IARC Scientific Publications

Figure 5. Value of contracts signed for competitive research grants in millions of USD

clear presentation of the changing cancer patterns worldwide. With this volume, much more use is made of the web rather than continued reliance on the printed volume. All tables previously found on printed page are now available on the electronic version which has many positive benefits. Before this new volume is made available in print, it is accessible online. The first volume in the fourth edition of the WHO Pathological Classification of Tumours (“Blue Books”) was published during 2007. This volume on “Tumours of the Central Nervous System” will be shortly followed by publication of the second volume on “Haematological Malignancies”. During the Biennium, IARC continued its international surveys of the prevalence of Human Papillomavirus (HPV ) types in many diverse regions of the world. Quality Control Guidelines for Cervix Cancer Screening were published and the results of a randomized trial of cervix cancer screening by visual inspection were published. This latter study, conducted in India, demonstrated the value of such a simple screening approach to significantly

reducing the incidence of invasive cervix cancer in a low-income setting. There have been many other important findings published in peer-reviewed scientific journals and these are discussed in more detail throughout this Report. IARC Working Group Reports There have been three Working Group reports (Green Books) published. The first concluded that exposure to artificial sources of sunlight for tanning purposes, such as sunbeds or sunlamps, at young ages was associated with an increased risk of melanoma. The second produced a comprehensive review of guidelines for Biological Resource Centres and focused on recommendations for minimal standards for the creation and organisation of such resources. A Working Group Report on “Attributable Causes of Cancer in France” was produced in conjunction with the Académie de Médecine and the Académie des Sciences of France. This employed as much French exposure data as possible and used

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Director’s Introduction

the classification base provided by the IARC Monographs and the IARC Handbook series to determine quantitatively the attributable fraction of cancer incidence and mortality in France attributable to identified causes. Tobacco and alcohol consumption emerged as the key causes of cancer in men. There are Working Groups on-going on “Vitamin D and Cancer Risk” and “The Global Cancer Burden Attributable to Asbestos” which are scheduled to report during 2008. Key Elements Research Training is a key element of the IARC Mission and the Research Training Fellowship Programme has been a major success since its inception. This has been supplemented with a Master’s and Doctoral Programme and the IARC Summer School is now an annual event in the IARC calendar. Eligibility for each programme is restricted to candidates from low- and medium-resource countries although for the Master’s Programme and Summer School candidates from highresource countries can attend but do not receive any financial support. While some students spend the entire time researching their Masters or PhD at IARC, there are many others who spend part of their programme here learning a technique or working on part of their assigned thesis project. During 2006-2007 five students obtained a Master’s degree and who spent more than half their programme working at the Agency. Eight students spent more that two years at IARC and obtained a doctoral degree: these students came from France, Australia, the Netherlands. IARC Ethics Committees A revised process of submitting and obtaining ethical approval for studies was introduced by the Governing Council in May 2005. Under the new structure, an IARC Institutional Review Board was created and an international Ethics Review Committee was established. There is a good interaction established between the two committees and this arrangement appears to be working in practice. The IRB met five times during 2007 and reviewed an average of eight projects at each meeting. xii

The Ethics Review Committee meets twice each year, once in Lyon, a joint meeting with the IRB, and once in a different Region of the world. In January 2007, the ERC met in Peru and had the opportunity to see at first hand the field conditions in which IARC Studies were conducted. In January 2008, the Ethics Committee will meet in Mumbai, India where there are a number of on-going IARC studies centred. The Ethics Review Committee was given a new task by the IARC Governing Council to monitor those IARC studies which have industrial funding. Expanding IARC activities in lowresource settings IARC has always had research activities in low-resource countries and this work is now expanding. Looking ahead, with the rapidly rising cancer burden in low-income and medium-income countries more highquality incidence data are needed from regions and countries in such settings. Reliable data are needed to establish the cancer burden and to monitor its evolution in all parts of the world, particularly in response to cancer control activities. Nurturing the development of cancer registration in such countries is of major importance and one which the International Agency for Research on Cancer is addressing. IARC has long-standing associations with Cancer Registries in low-resource settings and a meeting was held in Lyon (2007) with representatives from Africa, Asia and Latin America. The purpose was to identify ways in which IARC could assist in the development of cancer registration in such low-resource settings. Discussion included the subject of a meeting which was held at IARC in July, 2007 to discuss how best to fund such cancer registries. As a result, IARC will be launching a competition whose outcome will be to provide long-term, stable funding for a small number of cancer registries in low-resource countries. Criteria have been established to evaluate the likely success and sustainability of cancer registries and these will be applied to applications. There are studies of cervix cancer ongoing in many parts of Asia and Africa,

both surveys of Human Papillomavirus infection and screening studies of cervix cancer, including randomised trials. IARC has extended its activity in Liver Carcinogenesis in low-resource countries in addition to the long-term Gambia Hepatitis Intervention Study. The randomized trial of Oral Cancer screening, in Trivandrum, India, is still being followed-up and there is a key study of Nasopharyngeal Cancer on-going in Indonesia and other parts of Asia. A new IARC Research Group will become functional in 2008 to act as a focal point for the coordination and expansion of the IARC portfolio in low-resource countries. Arrivals and Departures Two Group Heads resigned during the Biennium. Dr Zhao Qi Wang (IARC 1997-2006), who was head of the Gene Environment Biology Group, departed to take up a position of Professor at the University of Jenna, Germany. Dr Carolyn Dresler (IARC 2004-2006), who was Head of the Tobacco Group, resigned to take up a position within State Government in the United States. Two Acting Group Heads also resigned from the Agency. Dr Paola Pisani took up a post at Oxford University and Dr Rudolf Kaaks accepted a position as Head of Epidemiology at DKFZ in Heidelberg, Germany. All at IARC thank them for their service to IARC and wish them the very best for the future. Dr Hai Rim Shin (Republic of Korea) was appointed as Head of the Descriptive Epidemiology Analysis Group and Dr Maria-Paula Curado (Brazil) was appointed Head of the Descriptive Epidemiology Production Group. Dr Philippe Autier (Belgium) moved to become Head of the Epidemiology Methods and Support Group and Dr Zdenko Herceg (Croatia) was appointed to the position of Head of the Epigenetics Group. Dr Elisabeth Cardis (Canada) was confirmed as Head of the Radiation Group and Dr Lawrence von Karsa (United States of America) was confirmed as Head of the Screening Quality Control Group. Mr Markus Pasterk (Austria) was appointed to a new position of Scientific Coordinator.

Director’s Introduction

Interaction among IARC, WHO and other International Organisations The Director gave a Media Briefing at the United Nations in New York (April, 2007) which was well received. In this, the problem of the Globalisation of Cancer was emphasized. There was a meeting held in Lyon in September 2007 of WHO HQ Directors working in areas in common with IARC. This emphasized the extent of the collaborations which IARC had with many groups in Headquarters and we have agreed to hold this meeting every six months. In addition, IARC hosts an Annual Meeting with NonCommunicable Disease Directors from WHO Regional Offices to discuss mutual problems and how IARC can assist in cancer prevention research activities. IARC has also developed a strong partnership with the International Atomic Energy Agency (IAEA) on the Programme of Action on Cancer Therapy (PACT). Funded initially by the Nobel Prize Fund, this programme aims to deliver cancer prevention and treatment facilities to underserved communities worldwide. The initial focus is on the 30+

countries which do not have a single Radiotherapy machine and the IARC commitment is to provide or improve, cancer registration in such areas where facilities are provided and also to search for opportunities for the establishment of sustainable early detection programmes. Six countries have been selected in a pilot programme: Sri Lanka, Tanzania, Viet Nam, Nicaragua, Albania and Yemen.

Publications

Cardis E, Krewski D, Boniol M, Drozdovitch V, Darby SC, Gilbert ES, Akiba S, Benichou J, Ferlay J, Gandini S, Hill C, Howe G, Kesminiene A, Moser M, Sanchez M, Storm H, Voisin L, Boyle P (2006). Estimates of the cancer burden in Europe from radioactive fallout from the Chernobyl accident. Int J Cancer 119: 1224-1235.

Baglietto L, Jenkins MA, Severi G, Giles GG, Bishop DT, Boyle P and Hopper JL. Measures of familial aggregation depend on definition of family history: meta-analysis for colorectal cancer. J Clin Epidemiol 2006 Feb;59(2):114124. Boffetta P, McLaughlin JK, La Vecchia C., Autier P, Boyle P (2007). 'Environment' in cancer causation and etiological fraction: limitations and ambiguities. Carcinogenesis 28: 913-915. Boyle P. The Globalisation of Cancer. Lancet 2006; 368: 629-630 Boyle P, Ariyaratne MA, Barrington R, Bartelink H, Bartsch G, Berns A, de Valeriola D, Dinshaw KA, Eggermont AM, Gray N, Kakizoe T, Karki BS, Kaslar M, Kerr DJ, Khayat D, Khuhaprema T, Kim IH, Martin-Moreno J, McVie G, Park JG, Philip T, Ringborg U, Rodger A, Seffrin JR, Semiglazov V, Soo KC, Sun YT, Thomas R, Tursz T, Veronesi U, Wiestler O, Yoo KY, Zatonski W and Zhao P. Tobacco: deadly in any form or disguise. Lancet. 2006 May 27;367(9524): 1710-2.

IARC Medal of Honour In 2006, the fourteenth Roger Sohier Lecture was given by George Klein (Sweden); the third Richard Doll Lecture was given by Joseph Fraumeni Jr. (United States of America); and the second IARC Lecture was given by Dr Katayun Dinshaw (India). In 2007, the fifteenth Roger Sohier Lecture was given by Mariano Barbacid (Spain); the fourth Richard Doll Lecture was given by Dimitri Trichopoulos (Greece); and the third IARC Lecture was given by Dr LaSalle D. Leffalle, on behalf of Nancy Brinker who founded the Komen Foundation, which celebrated its 25th Anniversary in 2007.

Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P (2007). Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 18: 581-592. Ferlay J, Randi G, Bosetti C, Levi F, Negri E, Boyle P, La Vecchia C. Declining mortality from bladder cancer in Europe. BJU Int. 2007 Oct 30; [Epub ahead of print] Hayes VM, Severi G, Padilla EJ, Morris HA, Tilley WD, Southey MC, English DR, Sutherland RL, Hopper JL, Boyle P, Giles GG (2007). 5alpha-Reductase type 2 gene variant associations with prostate cancer risk, circulating hormone levels and androgenetic alopecia. Int J Cancer 120: 776-780. Koutros S, Zhang Y, Zhu Y, Mayne ST, Zahm SH, Holford TR, Leaderer BP, Boyle P, Zheng

Each has made a significant contribution to cancer research and prevention and all received the IARC Medal of Honour. Participating States During the biennium a further four Participating States were admitted to the Agency: Republic of India, Republic of Korea, the Russian Federation and Ireland. This brings the number of Participating States to 20. This expansion of the Agency’s membership also introduces a new dimension into the governance structure of the Agency. Cancer is no longer a disease of highresource, industrialized, western countries as was the case when the IARC was founded forty years ago. Today the majority of the world cancer burden occurs in low- and medium-resource countries and the Agency must adopt a new focus of activity in the face of this development. The adhesion of new Participating States is a vote of confidence in the aims and activities of the Agency.

T. Nutrients Contributing to One-Carbon Metabolism and Risk of Non-Hodgkin Lymphoma Subtypes. Am J Epidemiol. 2007 Lan Q, Zheng T, Chanock S, Zhang Y, Shen M, Wang SS, Berndt SI, Zahm SH, Holford TR, Leaderer B, Yeager M, Welch R, Hosgood D, Boyle P, Rothman N (2007). Genetic variants in caspase genes and susceptibility to non-Hodgkin lymphoma. Carcinogenesis 28: 823-827. Lan Q, Zheng T, Rothman N, Zhang Y, Wang SS, Shen M, Berndt SI, Zahm SH, Holford TR, Leaderer B, Yeager M, Welch R, Boyle P, Zhang B, Zou K, Zhu Y and Chanock S. Cytokine polymorphisms in the Th1/Th2 pathway and susceptibility to non-Hodgkin lymphoma. Blood. 2006 Jan 31; [Epub ahead of print] Lan Q, Zheng T, Shen M, Zhang Y, Wang SS, Zahm SH, Holford TR, Leaderer B, Boyle P, Chanock S (2007). Genetic polymorphisms in the oxidative stress pathway and susceptibility to non-Hodgkin lymphoma. Hum Genet 121: 161-168.

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Director’s Introduction Robertson C, Link CL, Onel E, Mazzetta C, Keech M, Hobbs R, Fourcade R, Kiemeney L, Lee C, Boyle P and McKinlay JB. The impact of lower urinary tract symptoms and comorbidities on quality of life: the BACH and UREPIK studies. BJU Int. 2007 Feb;99(2):347-54. Scully C, Boyle P, Day T, Hill B, Joshi V, Leupold NE, Shah JP and Lefebvre JL. International Consortium on Head and Neck Cancer Awareness (ICOHANCA). Oral Oncol 2007: Oct;43(9):841-842. Severi G, Hayes VM, Neufing P, Padilla EJ, Tilley WD, Eggleton SA, Morris HA, English DR, Southey MC, Hopper JL, Sutherland RL, Boyle P and Giles GG. Variants in the prostatespecific antigen (PSA) gene and prostate cancer risk, survival, and circulating PSA. Cancer Epidemiol Biomarkers Prev. 2006 Jun;15(6): 1142-7. Severi G, Hayes VM, Tesoriero AA, Southey MC, Hoang HN, Padilla EJ, Morris HA, English DR, Sutherland RL, Boyle P, Hopper JL, Giles GG. The rs743572 common variant in the promoter of CYP17A1 is not associated with prostate cancer risk or circulating hormonal levels. BJU Int. 2007 Nov 6; [Epub ahead of print]

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Severi G, Morris HA, MacInnis RJ, English DR, Tilley WD, Hopper JL, Boyle P and Giles GG. Circulating insulin-like growth factor-I and binding protein-3 and risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2006 Jun;15(6):1137-41. Severi G, Morris HA, MacInnis RJ, English DR, Tilley W, Hopper JL, Boyle P and Giles GG. Circulating steroid hormones and the risk of prostate cancer. Cancer Epidemiol Biomarkers Prev. 2006 Jan;15(1):86-91 Shen M, Zheng T, Lan Q, Zhang Y, Zahm SH, Wang SS, Holford TR, Leaderer B, Yeager M, Welch R, Kang D, Boyle P, Zhang B, Zou K, Zhu Y, Chanock S, Rothman N. Polymorphisms in DNA repair genes and risk of non-Hodgkin lymphoma among women in Connecticut. Hum Genet. 2006 Jul;119(6): 659-68. Veronesi U, Maisonneuve P, Rotmensz N, Bonanni B, Boyle P, Viale G, Costa A, Sacchini V, Travaglini R, D'Aiuto G, Oliviero P, Lovison F, Gucciardo G, del Turco MR, Muraca MG, Pizzichetta MA, Conforti S, Decensi A; Italian Tamoxifen Study Group. Tamoxifen for the prevention of breast cancer: late results of the Italian Randomized Tamoxifen Prevention Trial among women with hysterectomy. J Natl Cancer Inst. 2007 May 2;99(9):727-37.

Zatonski W, Mikucka M, La Vecchia C and Boyle P. Infant mortality in Central Europe: effects of transition. Gac Sanit. 2006 JanFeb;20(1):63-6. Zhang Y, Holford TR, Leaderer B, Boyle P, Zhu Y, Wang R, Zou K, Zhang B, Wise JP, Qin Q, Kilfoy B, Han J, Zheng T (2007). Ultraviolet radiation exposure and risk of nonHodgkin's lymphoma. Am J Epidemiol 165: 1255-1264. Zhang Y, Wang R, Holford TR, Leaderer B, Zahm SH, Boyle P, Zhu Y, Qin Q, Zheng T (2007). Family history of hematopoietic and non-hematopoietic malignancies and risk of non-Hodgkin lymphoma. Cancer Causes Control 18: 351-359. Zhu Y, Leaderer D, Guss C, Brown HN, Zhang Y, Boyle P, Stevens RG, Hoffman A, Qin Q, Han X and Zheng T. Ala394Thr polymorphism in the clock gene NPAS2: A circadian modifier for the risk of nonHodgkin's lymphoma. Int J Cancer. 2007 ( Jan 15); 120(2) :432-5. Zhu Y, Zheng T, Stevens RG, Zhang Y and Boyle P. Does "clock" matter in prostate cancer? Cancer Epidemiol Biomarkers Prev. 2006 Jan;15(1):3-5.

IARC Scientific Structure Director Dr Peter Boyle

Biostatistics and Epidemiology Cluster (BEC) Dr Philippe Autier

Epidemiology and Biology Cluster (EBC) Dr Silvia Franceschi

Molecular Carcinogenesis Cluster (MCC) Dr Pierre Hainaut

Genetics and Epidemiology Cluster (GEC) Dr Paolo Boffetta

Pathogenesis and Prevention Cluster (PPC) Dr Hiroko Ohgaki

Data Analysis and Interpretation Group (DEA) Dr Hai-rim Shin

Infections and Cancer Biology Group (ICB) Dr Massimo Tommasino

Carcinogen Identification and Evaluation Group (CIE) Dr Vincent Cogliano

Genetic Epidemiology Group (GEP) Dr Paul Brennan

Pathology Group (PAT) Dr Hiroko Ohgaki

Descriptive Epidemiology Production Group (DEP) Dr Maria-Paula Curado

Infections and Cancer Epidemiology Group (ICE) Dr Silvia Franceschi

Epigenetics Group (EGE) Dr Zdenko Herceg

Genetic Susceptibility Group (GSC) Dr Sean Tavtigian

Screening Group (SCR) Dr Rengaswamy Sankaranarayanan

Epidemiology Methods and Support Group (BIO) Dr Philippe Autier

Nutrition and Hormones Group (ICE) Dr Silvia Franceschi (Acting)

Molecular Carcinogenesis and Biomarkers Group (MCB) Dr Pierre Hainaut

Lifestyle, Environment and Cancer Group (GEE) Dr Paolo Boffetta

Screening Quality Control Group (ECN) Dr Lawrence von Karsa

Reports to Office of the Director

Information Technology Services Group (ITS) Mr Michel Smans

Radiation Group (RAD) Dr Elisabeth Cardis

Office of the Director Scientific Coordination Office (SCO) Mr Markus Pasterk

Gambia Hepatitis Intervention Study (GHIS) Dr Pierre Hainaut

The Cabinet Dr P. Autier, Cluster Coordinator Dr P. Boffetta, Cluster Coordinator Dr S. Franceschi, Cluster Coordinator Dr P. Hainaut, Cluster Coordinator Dr H. Ohgaki, Cluster Coordinator Dr S. Tavtigian, Member without portfolio Mr M. Pasterk, Scientific Coordinator Mr M. Johnson, Director of Administration and Finance Dr P. Boyle, Director

Communications Group (COM) Dr Nicolas Gaudin

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Biostatistics and Epidemiology Cluster (BEC) Cluster Coordinator: Dr Philippe Autier The Biostatistics and Epidemiology Cluster (BEC) comprises five Groups: the Epidemiology Methods and Support Group (BIO), The Data Analysis and Interpretation Group (DEA), the Descriptive Epidemiology Production Group (DEP), the Information Technology Services Group (ITS) and the Radiation Group (RAD). One of the important goals of this Cluster is communicating information about cancer to the public. This is a principal focus of the Data Analysis and Interpretation (DEA) Group, headed by Hai-Rim Shin. The Descriptive Epidemiology Production (DEP) Group, headed by Maria-Paula Curado, analyses data describing cancer incidence, mortality and survival to identify and clarify the role of etiological factors in cancer. The Group works closely with cancer registries and national statistics systems to assemble data on incidence, survival and mortality and to ensure that these data are coherent and accurate. The Epidemiology Methods and Support Group (BIO), headed by Philippe Autier, combines expertise in mapping and analysis of epidemiological data and temporal trends with statistical methods for time-projection of data on cancer incidence and mortality. These competencies are developed and improved in the course of conducting multiple

ongoing projects in the BIO Group as well as in other Groups at IARC. The Information Technology Services (ITS) Group, headed by Michel Smans, exists to manage the central computing framework at IARC. This ranges from responding to the needs of individual users, to managing centralised services for statistical analysis, database storage, management and access to establishing new scientific and management systems for the Agency. Exposure to electromagnetic fields and ionizing radiation is a ubiquitous part of daily life, and the Radiation Group (RAD), headed by Elisabeth Cardis, exists to conduct targeted epidemiological studies of particular types of exposure. These studies not only respond to the needs of the scientific community, but also serve to address widespread concerns in the general population. All in all, the projects of the Cluster address 11 specific research areas: 1. Methods in biostatistics; 2. Methods in cancer registration; 3. Descriptive epidemiology; 4. Etiological hypothesis for selected cancers (e.g. of the testis); 5. Evaluation of the impact of screening and of treatments on incidence and mortality; 6. Attributable causes of cancer; 7. Skin cancer and ultraviolet radiation; 8. Vitamin D and cancer;

9. Evaluation of methods for cancer detection; 10. Ionizing radiation and cancer; and 11. Non-ionizing radiation (other than UV) and cancer. These projects are relevant to the overall mission of the IARC, as they contribute to the search for the causes of cancer. More specifically, the activities of the BEC Cluster compile data from around the world aiming at assessing the burden of cancer and evaluating cancer control efforts. Other BEC activities directly address known or possible causes of cancer and investigate possible methods for preventing and detecting cancer. Thus BEC activities reflect several parts of IARC’s mission: emphasis on the incidence and impact of human cancer; elucidation of the causes of cancer; prevention and early detection; and methodological research. The BEC cluster also participates in training activities, such as training cancer registries worldwide in standardised methods for data collection. There is a great deal of symbiosis among the five different Groups in the Cluster, which work closely together on many projects. Therefore, a project assigned to a specific group may be coordinated by a scientist of another group if such a structure will maximise the efficiency and scientific benefit of the project.

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Epidemiology Methods and Support Group (BIO) Head Dr Philippe Autier (since 01/2007) - Head of BEC Cluster since 09/2006 Mr Michel Smans (acting until 12/2006) Scientists Dr Mathieu Boniol (since 09/2006) Ms Geneviève Deharveng Dr Pietro Ferrari Dr Mazda Jenab (until 07/2007) Dr Rudolf Kaaks (until 07/2006) Dr Sabina Rinaldi Dr Nadia Slimani (from 05/2007) Dr Marit van Bakel (from 08/20006 to 05/2007) Clerks Ms Myriam Adjal (since 02/2007) Ms Murielle Colombet (since 04/2006) Secretariat Ms Asiedua Asante

The Epidemiology Methods and Support Group (BIO) exists at IARC to provide analysis, management, coordination of data collection, management and technical support for its biological material storage. The group encompasses the former Biostatistics Group and is currently made up of the Epidemiological Support Team (EST) and the Nutritional and Database Resource Team (NTR), with a new Biostatistics Team to be created in the future. Epidemiological Support Team The EST is working on several large projects funded by grants by the European Commission.

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Mrs Anne Sophie Hameau (since 06/2007) Ms Fatiha Louled (until 4 October 2007) Ms Laurence Marnat (until 05/2006) Mrs Sarah Somerville (until 13 March 2006) Technical Assistants Mr David Achaintre Ms Lucile Alteyrac Ms Priscilia Amouyal (until 10/2006) Ms Carine Biessy Mrs Josiane Bouzac (until 07/2006) Ms Corrine Casagrande Mr Thomas Cler (until 02/2007) Mr Sébastien Cuber (until 06/2006) Mrs Geneviève Deharveng (from 08/2006) Ms Laure Dossus (until 07/2006) Mr Bertrand Hemon Mr Mathieu Mazuir (from 04/2006 to 05/2006) Mr Jérôme Vignat

Exposure to ultraviolet radiation (UV ) and skin cancer EST has international expertise on sun protection, sun exposure, sunscreen use, and risk of melanoma and non melanoma skin cancer, and regularly publishes on these topics. EST staff are active members of international societies on skin cancer such as Euroskin and the EORTC Melanoma Group. EST staff are regularly invited to present worldwide at all of the major conferences on this topic. Most recently, staff were present at conferences hosted by the European Society of Skin Cancer Prevention and by the Karolinska

Visiting Scientists Dr Gary Fraser (from 05/2006 to 06/2006) Dr Sara Gandini Prof Daniel Krewski Dr Ivan Plesko Dr Jonathan Wakefield Prof Witold Zatonski Prof Tongzhang Zheng Students Mr Mustafa Al-Zoughool (until 08/2006) Ms Mariana Castillo-Beltran (until 08/2007) Mrs Inge Huybrechts (from 02/2007) Mr Anthony Montella (from 03/2007 to 08/2007) Consultant Dr Rodolfo Saracci

Institutet. Multiple articles have also been published on this topic. The most recent project on the UV/skin cancer topic is the “Quantification of sun exposure in Europe and its effects on health”, known as the Eurosun Project, a three-year project designed to monitor ultraviolet exposure in the European Union and its effects on the incidence of skin cancers and cataracts. Meteorological satellite data will be used to calculate exposure to various UV wavelengths for European populations; these data will be used to produce an atlas of UV exposure in Europe. These data will also serve to predict the global EU burden

Epidemiology Methods and Support Group

of UV-related diseases in the future. Concurrent with this project is a similar one, limited to France, funded by AFSSET (Agence Française de Sécurité Sanitaire de l’Environnement et du Travail, Paris). IARC working group on avoidable causes of cancer in France This group contributes to the elaboration of bio-statistical methods to estimate the proportion of cancer caused by major risk factors. Its main interests are to estimate attributable fractions for multiple categories of exposure, including continuous exposure, as well as considering interaction between risk factors and statistical uncertainties. In July 2005, a workshop at IARC brought together cancer epidemiologists who concluded that studies on attributable causes of cancer should begin by examining a few selected countries in the five continents. In September 2005, the French Académie Nationale de Médecine and the French Académie des Sciences proposed to IARC to collaborate on a study on attributable causes of cancer in France. This work took two years and involved a considerable number of collaborators in France and other countries. The results of the study were made public in September 2007, and the full report is available on the IARC website. The conclusion of the report is that about 40% and 25% of cancers occurring today in French men and women, respectively, are attributable to specific causes (and therefore theoretically preventable); it also stresses the limitations of current knowledge on human carcinogenesis. While it is expected that in the future the evidence in favour of or against a role of other risk factors will accumulate and eventually contribute to elucidating their contribution to human cancer, recommendations can be formulated to improve this process. Vitamin D and cancer A Working Group on Vitamin D is currently being established to examine the possible association between vitamin D and cancer. This Working Group is reviewing the epidemiological and laboratory evidence and will try to come up with consensus evaluations, with results beginning to be published early in 2008.

Given the controversies and the polarisation of opinions on this subject, we have set up a group of independent researchers of international reputation. We did not only seek experts in Vitamin D issues, but also senior scientists with extensive experience in laboratory and epidemiological studies. The IARC secretariat will review the articles and prepare a draft working document which will be reviewed and expanded upon by the Working Group members. Writing tasks have been distributed among Working Group members, and a FTP website with all the documentation has been created, representing the common library of the Working Group. Meta-analyses of studies on the effects of vitamin D on several different cancers are underway. A meeting in December 2007 has been devoted to sorting out points of disagreement, finding a consensus conclusion, and identifying the critical studies that are still needed for defining the role of vitamin D in cancer, including the need to mount randomised trials. The Group has attended the Health Strategies in Europe meeting (summer 2007) as well as the High Level Conference on the Future of Science and Technology in Europe (fall 2007), both held in Lisbon, in addition to being asked to present papers at multiple conferences, including ones on cancer and the environment and breast cancer. Eurocadet The EST is strongly involved in a European project called Eurocadet, which aims to contribute to the prevention of cancer in Europe via estimating the effects of successful implementation of prevention strategies on the incidence of cancer. BIO is responsible for two key work packages in this effort: The first work package has the responsibility of collecting data on prevalence of exposure to major established cancer risk factors in Europe. This data gathering benefits from the Group’s previous experience on the project evaluating avoidable causes of cancer in France. Preliminary analysis showed disparities on the evolution of risk factors; for example, important differences exist in

Western Europe with Nordic countries presenting great success in tobacco control whereas Southern European countries are only beginning to get results on tobacco smoking. It also revealed the emergence of an epidemic in Central Europe with important increases in tobacco smoking among both men and women. This work package is finalising the database on prevalence of risk factors in Europe and preparing scientific publications of these data. The second work package is dedicated to estimating projections of incidence and mortality from cancer in Europe from 2005 to 2015 based on data from cancer registries. These estimations were finalised for 2006 in a preliminary study (Estimates of the cancer incidence and mortality in Europe in 2006). Statistical method for analysis of cancer incidence, mortality and temporal changes The group is closely linked to the activities of the DEP and DEA Groups to provide statistical supervision of incidence, mortality and time trend analysis. Time trend analysis requires everything from joinpoint regression used in descriptive epidemiology (such as those performed in the analysis of trends in breast cancer incidence and mortality) to more complex explorative methods. Within the Working Group on cancer following the Chernobyl accident, the group developed a statistical analysis of time trends of cancer incidence and mortality with an age-period-cohort model applied to multiple countries. In this project random effect models of cancer incidence and mortality were also built to disentangle residual country effects from doses of radiation. Another activity concerns the estimation of incidence worldwide—the group is a member of the Cancer Incidence in Five Continents (CI5) Volume IX group. BIO developed methods based on principal component analysis to identify sources of variability in the database and to clear errors that could be missed by regular checking for outliers. The BIO Group also provided statistical support for statistics used in CI5. This activity led the group to evaluate current data on non-melanoma skin cancer in the world. This cancer site is 3

Biostatistics and Epidemiology Cluster

a forgotten cancer in many reports, and a specific report was produced on worldwide incidence of non-melanoma skin cancer. The BIO Group is involved in various international collaborations, such as those which resulted in the epidemiological publications Lung Cancer and Cannabis in Tunisia and in Maghreb and Tobacco Smoking and Cancer: A Meta-Analysis. Other activities of EST EST is an active participant in the IARC Summer School program. In addition, over the last two years the BIO Group has provided regular statistical support to other IARC groups. Nutrition and Hormone Team (NTR) The NTR team has three axes of activities: 1) Support the coordination and management of EPIC, including the maintenance of its central database; 2) Conduct advanced research on dietary and statistical methodologies and laboratory activities relevant to international epidemiological studies; 3) Conduct research on diet, metabolic factors and cancer and other chronic diseases. Support the coordination and management of the EPIC network Over the last two years, the NTR team has ensured technical support and preparation of a series of common and project-specific datasets for a large network of 25 EPIC working groups and related projects (e.g. EPIC coordination project, INTERACT, Diogenes, EuroGast, EPIC-Elderly, Panscan, breast and prostate cohort consortium). In particular, an update of the

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follow-up cancer and mortality data and other dietary and lifestyle variables was circulated to the EPIC network in March 2007. Advanced research methodologies and laboratory activities A major focus for the NTR team is to develop methods for the standardised dietary data collection, data processing and statistical analyses in large multi-centre studies. This involves the development of a highly standardised computerised 24-hour dietary recall programme (EPIC-SOFT), and more recently, the compilation of a standardised nutrient database (ENDB), containing 26 nutrients and ~10 000 foods from the 10 EPIC participating countries, as well as the development of a complex database management system programme (EnMan) to handle international nutrient databases. Two review papers on ENDB were published in 2007. In addition, the NTR team has developed statistical models to analyse diet-disease associations, after correction for measurement errors in dietary assessments. Over the years, the NTR team has answered continuously increasing requests to use its dietary methodologies, particularly after an independent EU working group (EFCOSUM) recommended EPIC-SOFT as the reference method for future pan-European surveys. During this biennium, the NTR team supported the implementation of the EPIC-SOFT methodology in different national and regional monitoring surveys in Germany, The Netherlands and Belgium. In addition, the team extended

its international collaborations through different recently funded EU projects (EFCOVAL, IDAMES, EuroFIR) in order to further develop and adapt the EPIC-SOFT methodology for future large international nutritional studies, including pan-European monitoring surveys. A fully operational upgraded EPIC-SOFT programme is expected to be ready by 2009 through the on-going EFCOVAL project. In parallel, the feasibility of adapting EPIC-SOFT to non-European countries (e.g. India) has been initiated through an IARC project coordinated by P. Boffetta. In addition, new standardised databases on glycemic index/glycemic load, animal/plant proteins and fats have been developed to extend the reach of nutritional research activities. The development of an acrylamide database is also ongoing. The NTR team has been involved in the coordination of the EPIC statistical working group. The group intends to provide scientists in the EPIC network with guidelines for the analysis of the relationship between dietary and nondietary factors and disease outcomes. In addition, the group is conducting forefront methodological research in the field of nutritional epidemiology. In April 2007, a workshop meeting was held in Lyon, with the participation of over 20 statisticians working in the EPIC network, as well as a number of scientists worldwide. The meeting focused on three main research aspects: the evaluation of the diet/disease association in multi-centric studies, measurement error correction procedures for the diet/disease association, and the definition of statistical technique for the search of dietary patterns. Another important responsibility of the NTR team is its laboratory activity support for hormone analyses for large epidemiological studies. Over the last biennium, the laboratory has focussed mainly on the measurements of sex steroids, growth factors and C-peptide of insulin, as well as of adiponectin and leptin, in serum or plasma samples from several large-scale epidemiological studies, including EPIC. In addition to routine analyses, a very sensitive method for the measurements of circulating estrogens and estrogen metabolites (hydroxy and

Epidemiology Methods and Support Group

methoxy estrogens) in serum and in urine samples using negative chemical ionisation gas chromatography/mass spectrometric detection has been set up. The NTR team was also involved in validating the stability of nutritional biomarkers such as vitamin C, vitamin D status, iron status and oxidative stress by comparing measurements from EPIC blood samples stored for many years under liquid nitrogen and those taken at earlier time intervals before or during storage. Furthermore, a complex Laboratory Information Management System (LIMS) has also been developed to handle biological samples movements and related results. Initially developed for EPIC, this LIMS will also be used for other IARC projects. Research activities Cross-sectional studies on diet and biomarkers of diet. The NTR team is coordinating the preparation of a Special issue on Nutrient Intakes and Patterns in EPIC (SNIPE) of 15 papers to be published by summer 2008, as a principal activity of the nutritional EPIC working group led by the NTR team. Over this biennium, a series of common and paper-specific databases, as well as common guidelines and SAS programs, were prepared to support this project. Team scientists were also involved in major cross-sectional analyses of blood phytoestrogen, acrylamide and fatty acids levels, and consumption patterns and portion sizes of nuts and seeds across Europe. Diet and cancer. A major role of the NTR team is to use data from the EPIC study

to investigate the association of diet and nutrition with risk of cancers, particularly those of the colorectum, stomach and prostate. Team scientists have led studies showing that increased intake of alcohol, both at baseline and over a lifetime, is associated with higher risk of colorectal cancer. As a follow-up to these findings, the team is leading a study on polymorphisms in genes regulating the metabolism of alcohol. Another NTR-led study showed that higher blood concentrations of some carotenoids and vitamin C are associated with a decreased risk of gastric cancer through, for vitamin C, inhibition of endogenous n-nitroso compound formed from high intake of red and processed meats. The team has also had a major collaborative role in studies showing that higher blood levels of vitamin B12 (but not folate) are associated with decreased risk, and also that higher blood levels of carotenoids, including lycopene, are not associated with localized prostate cancer, but were significantly associated with risk of advanced disease. Other research projects on blood concentrations of vitamin D, body iron status, oxidative stress parameters and blood lipid profiles in relation to risk of colorectal cancers are on-going. More advanced studies ready to be submitted show that higher intake of dietary fat, particularly monounsaturated fats, is associated with an increased risk of gastric cancer, particularly in northern European countries where monounsaturated fat is mostly derived from meats and meat products. These results were confirmed by

measurement of blood phospholipid fatty acid profiles, showing that higher blood levels of oleic acid, the main monounsaturated fat in the blood stream, is associated with increased gastric cancer risk. Hormones and cancer. In the current biennium, this research has focused on cancers of the endometrium, ovary and prostate cancers. An EPIC nested casecontrol study on endometrial cancer showed about a two-fold increase in cancer risk with increasing prediagnostic serum C-peptide concentrations, with elevated glucose levels and with low HDL levels in blood and lower concentrations of adiponectin. Obesity and greater adult weight gain were also associated with increased risk of endometrial cancer, supporting further that hyperinsulinemia and obesity are risk factors for this cancer. This team has also shown that higher blood levels of C-peptide, a marker of insulin release, as well as elevated measures of glycosylated haemoglobin, are associated with increased risk of colorectal cancers. In another nested case-control study, elevated serum levels of IGF-I were associated with a strong increase in ovarian cancer in premenopausal women with an ovarian cancer diagnosed at a relative young age. Similarly, in EPIC and in the US PLCO cohort study, endogenous concentrations of IGF-I were not strongly associated with prostate cancer risk, although the association with risk was more pronounced for advanced-stage or aggressive disease.

The BIO Group is grateful to the following for their collaboration in its projects: Sara Gandini - IEO, Milan, Italy; Jan Willem Coeberg - Erasmus University, Rotterdam, Netherlands; Anna Gavin - Northern Ireland Cancer registry, Belfast, Ireland; Laufey Triggvadottir - Icelandic Cancer Society, Reykjavik, Iceland; Lucien Wald - Ecole des Mines de Paris, Sophia Antipolis, France; Eduardo Roseblatt - IAEA, Vienna, Austria; Maurice Tubiana - Académie de Médecine, Paris, France; Julian Peto - London School of Hygiene and Tropical Medicine, London, UK. Financial Support from the following bodies is gratefully acknowledged: Agence Française de Sécurité Sanitaire de l'Environnement et du Travail (AFSSET), Directorate General for Health and Consumer Protection of the European Commission (DG Sanco), Directorate General for Research of the European Commission (DG Research), World Cancer Research Fund International (WCRF)

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Biostatistics and Epidemiology Cluster

Publications

Int J Cancer. Epub ahead of print.

Arbyn M, Raifu AO, Autier P, Ferlay J (2007). Burden of cervical cancer in Europe: estimates for 2004. Ann Oncol. Oct;18(10):1708-1715.

International Agency for Research on Cancer Working Group on artificial ultraviolet (UV) light and skin cancer, Autier P, Boniol M, Boyle P, Daniel J, Dore JF, Gandini S, Green A, Newton-Bishop J, Weinstock MA, Westerdahl J, Secretan B, Walter SD (2006). The association of use of sunbeds with cutaneous malignant melanoma and other skin cancers: A systematic review. Int J Cancer;120:1116–1122.

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International Agency for Research on Cancer (2007). Attributable Causes of Cancer in France in the year 2000. Report from an IARC Working Group, Lyon. Pedeux R, Sales F, Pourchet J, Kallassy M, Fayolle C, Boniol M, Severi G, Ghanem G, Nakazawa HN, Autier P, Dore JF (2006). Ultraviolet B sensitivity of peripheral lymphocytes as an independent risk factor for cutaneous melanoma. Eur J Cancer;42(2):212215. Scelo G, Boffetta P, Autier P, Hemminki K, Pukkala E, Olsen JH Weiderpass E, Tracey E, Brewster DH, McBride ML, Kliewer EV, Tonita JM, Pompe-Kirn V, Chia KS, Jonasson JG, Martos C, Giblin M, Brennan P (2007). Associations between ocular melanoma and other primary cancers: an international population-based study. Int J Cancer;120:151159. Voirin N, Berthillet J, Benhaim-Luzon V, Boniol M, Straif K, Ben Ayoud W, Ben Ayed F, Sasco A (2006). Risk for lung cancer and past use of cannabis in Tunisia. J Thorac Oncol;1:577– 579. Nutritional and Database Resource Team Agudo A, Sala N, Pera G, Capella G, Berenguer A, Garcia N, Palli D, Boeing H, Del Giudice G, Saieva C, Carneiro F, Berrino F, Sacerdote C, Tumino R, Panico S, Berglund G, Siman H, Stenling R, Hallmans G, Martinez C, Bilbao R, Barricarte A, Navarro C, Quiros JR, Allen N, Key T, Bingham S, Khaw KT, Linseisen J, Nagel G, Overvad K, Tjonneland A, Olsen A, Buenode-Mesquita HB, Boshuizen HC, Peeters PH, Numans ME, Clavel-Chapelon F, BoutronRuault MC, Trichopoulou A, Lund E, Offerhaus J, Jenab M, Ferrari P, Norat T, Riboli E, Gonzalez CA (2006).Polymorphisms in metabolic genes related to tobacco smoke and the risk of gastric cancer in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev.;15(12):2427-2434. Agudo A, Sala N, Pera G, Capella G, Berenguer A, Garcia N, Palli D, Boeing H, Del Giudice G, Saieva C, Carneiro F, Berrino F, Sacerdote C, Tumino R, Panico S, Berglund G, Siman H,

Stenling R, Hallmans G, Martinez C, Amiano P, Barricarte A, Navarro C, Quiros JR, Allen N, Key T, Bingham S, Khaw KT, Linseisen J, Nagel G, Overvad K, Tjonneland A, Olsen A, Buenode-Mesquita HB, Boshuizen HC, Peeters PH, Numans ME, Clavel-Chapelon F, BoutronRuault MC, Trichopoulou A, Lund E, Blaker H, Jenab M, Ferrari P, Norat T, Riboli E, Gonzalez CA (2006). No association between polymorphisms in CYP2E1, GSTM1, NAT1, NAT2 and the risk of gastric adenocarcinoma in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev;15(5):1043-1045. Al-Delaimy WK, Jansen EH, Peeters PH, van der Laan JD, van Noord PA, Boshuizen HC, van der Schouw YT, Jenab M, Ferrari P, Buenode-Mesquita HB (2006). Reliability of biomarkers of iron status, blood lipids, oxidative stress, vitamin D, C-reactive protein and fructosamine in two Dutch cohorts. Biomarkers;11(4):370-382. Allen NE, Key TJ, Appleby PN, Travis RC, Roddam AW, Rinaldi S, Egevad L, Rohrmann S, Linseisen J, Pischon T, Boeing H, Johnsen NF, Tjonneland A, Gronbaek H, Overvad K, Kiemeney L, Bueno-de-Mesquita HB, Bingham S, Khaw KT, Tumino R, Berrino F, Mattiello A, Sacerdote C, Palli D, Quiros JR, Ardanaz E, Navarro C, Larranaga N, Gonzalez C, Sanchez MJ, Trichopoulou A, Travezea C, Trichopoulos D, Jenab M, Ferrari P, Riboli E, Kaaks R (2007). Serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 concentrations and prostate cancer risk: results from the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiol BiomarkersPrev; 16(6):1121-1127. Al-Zoughool M, Dossus L, Kaaks R, ClavelChapelon F, Tjonneland A, Olsen A, Overvad K, Boutron-Ruault MC, Gauthier E, Linseisen J, Chang-Claude J, Boeing H, Schulz M, Trichopoulou A, Chryssa T, Trichopoulos D, Berrino F, Palli D, Mattiello A, Tumino R, Sacerdote C, Bueno-de-Mesquita HB, Boshuizen HC, Peeters PH, Gram IT, Braaten T, Lund E, Chirlaque MD, Ardanaz E, Agudo A, Larranaga N, Quiros JR, Berglund G, Manjer J, Lundin E, Hallmans G, Khaw KT, Bingham S, Allen N, Key T, Jenab M, Cust AE, Rinaldi S, Riboli E (2007). Risk of endometrial cancer in relationship to cigarette smoking: Results from the EPIC study. Int J Cancer. Jul 26; [Epub ahead of print] Bamia C, Trichopoulos D, Ferrari P, Overvad K, Bjerregaard L, Tjonneland A, Halkjaer J, ClavelChapelon F, Kesse E, Boutron-Ruault MC, Boffetta P, Nagel G, Linseisen J, Boeing H, Hoffmann K, Kasapa C, Orfanou A, Travezea C, Slimani N, Norat T, Palli D, Pala V, Panico S, Tumino R, Sacerdote C, Bueno-de-Mesquita

Epidemiology Methods and Support Group HB, Waijers PM, Peeters PH, van der Schouw YT, Berenguer A, Martinez-Garcia C, Navarro C, Barricarte A, Dorronsoro M, Berglund G, Wirfalt E, Johansson I, Johansson G, Bingham S, Khaw KT, Spencer EA, Key T, Riboli E, Trichopoulou A. (2007). Dietary patterns and survival of older Europeans: the EPIC-Elderly Study (European Prospective Investigation into Cancer and Nutrition). Public Health Nutr.;10(6):590-598. Berrington de Gonzalez A, Spencer EA, Bueno-de-Mesquita HB, Roddam A, Stolzenberg-Solomon R, Halkjaer J, Tjonneland A, Overvad K, Clavel-Chapelon F, Boutron-Ruault MC, Boeing H, Pischon T, Linseisen J, Rohrmann S, Trichopoulou A, Benetou V, Papadimitriou A, Pala V, Palli D, Panico S, Tumino R, Vineis P, Boshuizen HC, Ocke MC, Peeters PH, Lund E, Gonzalez CA, Larranaga N, Martinez-Garcia C, Mendez M, Navarro C, Quiros JR, Tormo MJ, Hallmans G, Ye W, Bingham SA, Khaw KT, Allen N, Key TJ, Jenab M, Norat T, Ferrari P, Riboli E (2006). Anthropometry, physical activity, and the risk of pancreatic cancer in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev;15(5):879-885. Boeing H, Dietrich T, Hoffmann K, Pischon T, Ferrari P, Lahmann PH, Boutron-Ruault MC, Clavel-Chapelon F, Allen N, Key T, Skeie G, Lund E, Olsen A, Tjonneland A, Overvad K, Jensen MK, Rohrmann S, Linseisen J, Trichopoulou A, Bamia C, Psaltopoulou T, Weinehall L, Johansson I, Sanchez MJ, Jakszyn P, Ardanaz E, Amiano P, Chirlaque MD, Quiros JR, Wirfalt E, Berglund G, Peeters PH, van Gils CH, Bueno-de-Mesquita HB, Buchner FL, Berrino F, Palli D, Sacerdote C, Tumino R, Panico S, Bingham S, Khaw KT, Slimani N, Norat T, Jenab M, Riboli E (2006). Intake of fruits and vegetables and risk of cancer of the upper aero-digestive tract: the prospective EPIC-study. Cancer Causes Control;17(7):957-969. Bremnes Y, Ursin G, Bjurstam N, Rinaldi S, Kaaks R, Gram IT (2007). Endogenous sex hormones, prolactin and mammographic density in postmenopausal Norwegian women. Int J Cancer;26 [Epub ahead of print] PMID: 17657735 [PubMed - as supplied by publisher] Canzian F, McKay JD, Cleveland RJ, Dossus L, Biessy C, Rinaldi S, Landi S, Boillot C, Monnier S, Chajes V, Clavel-Chapelon F, Tehard B, Chang-Claude J, Linseisen J, Lahmann PH, Pischon T, Trichopoulos D, Trichopoulou A, Zilis D, Palli D, Tumino R, Vineis P, Berrino F, Bueno-de-Mesquita HB, van Gils CH, Peeters PH, Pera G, Ardanaz E, Chirlaque MD, Quiros JR, Larranaga N, Martinez-Garcia C, Allen NE, Key TJ,

Bingham SA, Khaw KT, Slimani N, Norat T, Riboli E, Kaaks R (2006). Polymorphisms of genes coding for insulin-like growth factor 1 and its major binding proteins, circulating levels of IGF-I and IGFBP-3 and breast cancer risk: results from the EPIC study. Br J Cancer;30;94(2): 299-307. Cox DG, Blanche H, Pearce CL, Calle EE, Colditz GA, Pike MC, Albanes D, Allen NE, Amiano P, Berglund G, Boeing H, Buring J, Burtt N, Canzian F, Chanock S, ClavelChapelon F, Feigelson HS, Freedman M, Haiman CA, Hankinson SE, Henderson BE, Hoover R, Hunter DJ, Kaaks R, Kolonel L, Kraft P, LeMarchand L, Lund E, Palli D, Peeters PH, Riboli E, Stram DO, Thun M, Tjonneland A, Trichopoulos D, Yeager M; Breast and Prostate Cancer Cohort Consortium (2006). A comprehensive analysis of the androgen receptor gene and risk of breast cancer: results from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium (BPC3). Breast Cancer Res;8(5):R54. Cust AE, Allen NE, Rinaldi S, Dossus L, Friedenreich C, Olsen A, Tjonneland A, Overvad K, Clavel-Chapelon F, Boutron-Ruault MC, Linseisen J, Chang-Claude J, Boeing H, Schulz M, Benetou V, Trichopoulou A, Trichopoulos D, Palli D, Berrino F, Tumino R, Mattiello A, Vineis P, Quiros JR, Agudo A, Sanchez MJ, Larranaga N, Navarro C, Ardanaz E, Bueno-de-Mesquita HB, Peeters PH, van Gils CH, Bingham S, Khaw KT, Key T, Slimani N, Riboli E, Kaaks R. (2007). Serum levels of Cpeptide, IGFBP-1 and IGFBP-2 and endometrial cancer risk; results from the European prospective investigation into cancer and nutrition. Int J Cancer;15;120(12):26562664.

Danesh J, Saracci R, Berglund G, Feskens E, Overvad K, Panico S, Thompson S, Fournier A, Clavel-Chapelon F, Canonico M, Kaaks R, Linseisen J, Boeing H, Pischon T, Weikert C, Olsen A, Tjonneland A, Johnsen SP, Jensen MK, Quiros JR, Svatetz CA, Perez MJ, Larranaga N, Sanchez CN, Iribas CM, Bingham S, Khaw KT, Wareham N, Key T, Roddam A, Trichopoulou A, Benetou V, Trichopoulos D, Masala G, Sieri S, Tumino R, Sacerdote C, Mattiello A, Verschuren WM, Bueno-de-Mesquita HB, Grobbee DE, van der Schouw YT, Melander O, Hallmans G, Wennberg P, Lund E, Kumle M, Skeie G, Ferrari P, Slimani N, Norat T, Riboli E; EPICHeart (2007). EPIC-Heart: the cardiovascular component of a prospective study of nutritional, lifestyle and biological factors in 520,000 middle-aged participants from 10 European countries. Eur J Epidemiol.;22(2):129-141. Dechaud H, Denuziere A, Rinaldi S, Bocquet J, Lejeune H, Pugeat M (2007). Age-associated discrepancy between measured and calculated bioavailable testosterone in men. Clin Chem;53(4):723-728. Engeset D, Alsaker E, Lund E, Welch A, Khaw KT, Clavel-Chapelon F, Thiebaut A, Chajes V, Key TJ, Allen NE, Amiano P, Dorronsoro M, Tjonneland A, Stripp C, Peeters PH, van Gils CH, Chirlaque MD, Nagel G, Linseisen J, Ocke MC, Bueno-de-Mesquita HB, Sacerdote C, Tumino R, Ardanaz E, Sanchez MJ, Panico S, Palli D, Trichopoulou A, Kalapothaki V, Benetou V, Quiros JR, Agudo A, Overvad K, Bjerregaard L, Wirfalt E, Schulz M, Boeing H, Slimani N, Riboli E (2006). Fish consumption and breast cancer risk. The European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer;1;119(1):175-182.

Cust AE, Kaaks R, Friedenreich C, Bonnet F, Laville M, Lukanova A, Rinaldi S, Dossus L, Slimani N, Lundin E, Tjonneland A, Olsen A, Overvad K, Clavel-Chapelon F, Mesrine S, Joulin V, Linseisen J, Rohrmann S, Pischon T, Boeing H, Trichopoulos D, Trichopoulou A, Benetou V, Palli D, Berrino F, Tumino R, Sacerdote C, Mattiello A, Quiros JR, Mendez MA, Sanchez MJ, Larranaga N, Tormo MJ, Ardanaz E, Bueno-de-Mesquita HB, Peeters PH, van Gils CH, Khaw KT, Bingham S, Allen N, Key T, Jenab M, Riboli E (2007). Plasma adiponectin levels and endometrial cancer risk in pre- and postmenopausal women. J Clin Endocrinol Metab; 92(1):255-263.

Feigelson HS, Cox DG, Cann HM, Wacholder S, Kaaks R, Henderson BE, Albanes D, Altshuler D, Berglund G, Berrino F, Bingham S, Buring JE, Burtt NP, Calle EE, Chanock SJ, Clavel-Chapelon F, Colditz G, Diver WR, Freedman ML, Haiman CA, Hankinson SE, Hayes RB, Hirschhorn JN, Hunter D, Kolonel LN, Kraft P, LeMarchand L, Linseisen J, Modi W, Navarro C, Peeters PH, Pike MC, Riboli E, Setiawan VW, Stram DO, Thomas G, Thun MJ, Tjonneland A, Trichopoulos D (2006). Haplotype analysis of the HSD17B1 gene and risk of breast cancer: a comprehensive approach to multicenter analyses of prospective cohort studies. Cancer Res; 15;66(4):2468-2475.

Cust AE, Armstrong BK, Friedenreich CM, Slimani N, Bauman A. (2007). Physical activity and endometrial cancer risk: a review of the current evidence, biologic mechanisms and the quality of physical activity assessment methods. Cancer Causes Control. 18(3):243-258.

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Biostatistics and Epidemiology Cluster Ferrari P, Jenab M, Norat T, Moskal A, Slimani N, Olsen A, Tjonneland A, Overvad K, Jensen MK, Boutron-Ruault MC, Rohrmann S, Linseisen J, Boeing H, Bergmann M, Kontopoulou D, Trichopoulou A, Kassapa C, Masala G, Krogh V, Vineis P, Panico S, Tumino R, Gils CH, Peeters P, Bueno-de-Mesquita HB, Ocke MC, Skeie G, Lund E, Agudo A, Ardanaz E, Lopez DC, Sanchez MJ, Quiros JR, Amiano P, Berglund G, Manjer J, Palmqvist R, Guelpen BV, Allen N, Key T, Bingham S, Mazuir M, Boffetta P, Kaaks R, Riboli E, Clavel-Chapelon F, Morois S (2007).Lifetime and baseline alcohol intake and risk of colon and rectal cancers in the European prospective investigation into cancer and nutrition (EPIC). Int J Cancer; Jul 19; [Epub ahead of print] PMID: 17640039 [PubMed - as supplied by publisher]. Friedenreich C, Cust A, Lahmann PH, Steindorf K, Boutron-Ruault MC, ClavelChapelon F, Mesrine S, Linseisen J, Rohrmann S, Pischon T, Schulz M, Tjonneland A, Johnsen NF, Overvad K, Mendez M, Arguelles MV, Garcia CM, Larranaga N, Chirlaque MD, Ardanaz E, Bingham S, Khaw KT, Allen N, Key T, Trichopoulou A, Dilis V, Trichopoulos D, Pala V, Palli D, Tumino R, Panico S, Vineis P, Bueno-de-Mesquita HB, Peeters PH, Monninkhof E, Berglund G, Manjer J, Slimani N, Ferrari P, Kaaks R, Riboli E (2007). Physical activity and risk of endometrial cancer: the European prospective investigation into cancer and nutrition. Int J Cancer; 15;121(2):347-355. Friedenreich C, Cust A, Lahmann PH, Steindorf K, Boutron-Ruault MC, ClavelChapelon F, Mesrine S, Linseisen J, Rohrmann S, Boeing H, Pischon T, Tjonneland A, Halkjaer J, Overvad K, Mendez M, Redondo ML, Garcia CM, Larranaga N, Tormo MJ, Gurrea AB, Bingham S, Khaw KT, Allen N, Key T, Trichopoulou A, Vasilopoulou E, Trichopoulos D, Pala V, Palli D, Tumino R, Mattiello A, Vineis P, Bueno-de-Mesquita HB, Peeters PH, Berglund G, Manjer J, Lundin E, Lukanova A, Slimani N, Jenab M, Kaaks R, Riboli E (2007). Anthropometric factors and risk of endometrial cancer: the European prospective investigation into cancer and nutrition. Cancer Causes Control; 18(4):399-413. Friedenreich C, Norat T, Steindorf K, BoutronRuault MC, Pischon T, Mazuir M, Clavel-Chapelon F, Linseisen J, Boeing H, Bergman M, Johnsen NF, Tjonneland A, Overvad K, Mendez M, Quiros JR, Martinez C, Dorronsoro M, Navarro C, Gurrea AB, Bingham S, Khaw KT, Allen N, Key T, Trichopoulou A, Trichopoulos D, Orfanou N, Krogh V, Palli D, Tumino R, Panico S, Vineis P, Bueno-de-Mesquita HB, Peeters PH, Monninkhof E, Berglund G, Manjer J, Ferrari 8

P, Slimani N, Kaaks R, Riboli E (2006). Physical activity and risk of colon and rectal cancers: the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev; 15(12):2398-2407. Gonzalez CA, Jakszyn P, Pera G, Agudo A, Bingham S, Palli D, Ferrari P, Boeing H, del Giudice G, Plebani M, Carneiro F, Nesi G, Berrino F, Sacerdote C, Tumino R, Panico S, Berglund G, Siman H, Nyren O, Hallmans G, Martinez C, Dorronsoro M, Barricarte A, Navarro C, Quiros JR, Allen N, Key TJ, Day NE, Linseisen J, Nagel G, Bergmann MM, Overvad K, Jensen MK, Tjonneland A, Olsen A, Bueno-de-Mesquita HB, Ocke M, Peeters PH, Numans ME, Clavel-Chapelon F, Boutron-Ruault MC, Trichopoulou A, Psaltopoulou T, Roukos D, Lund E, Hemon B, Kaaks R, Norat T, Riboli E( 2006). Meat intake and risk of stomach and esophageal adenocarcinoma within the European Prospective Investigation Into Cancer and Nutrition (EPIC). J Natl Cancer Inst; 1;98(5):345-354. Gonzalez CA, Pera G, Agudo A, Bueno-deMesquita HB, Ceroti M, Boeing H, Schulz M, Del Giudice G, Plebani M, Carneiro F, Berrino F, Sacerdote C, Tumino R, Panico S, Berglund G, Siman H, Hallmans G, Stenling R, Martinez C, Dorronsoro M, Barricarte A, Navarro C, Quiros JR, Allen N, Key TJ, Bingham S, Day NE, Linseisen J, Nagel G, Overvad K, Jensen MK, Olsen A, Tjonneland A, Buchner FL, Peeters PH, Numans ME, Clavel-Chapelon F, Boutron-Ruault MC, Roukos D, Trichopoulou A, Psaltopoulou T, Lund E, Casagrande C, Slimani N, Jenab M, Riboli E. (2006).Fruit and vegetable intake and the risk of stomach and oesophagus adenocarcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST). Int J Cancer; 15;118(10):2559-2566. Gram IT, Norat T, Rinaldi S, Dossus L, Lukanova A, Tehard B, Clavel-Chapelon F, van Gils CH, van Noord PA, Peeters PH, Buenode-Mesquita HB, Nagel G, Linseisen J, Lahmann PH, Boeing H, Palli D, Sacerdote C, Panico S, Tumino R, Sieri S, Dorronsoro M, Quiros JR, Navarro CA, Barricarte A, Tormo MJ, Gonzalez CA, Overvad K, Paaske Johnsen S, Olsen A, Tjonneland A, Travis R, Allen N, Bingham S, Khaw KT, Stattin P, Trichopoulou A, Kalapothaki V, Psaltopoulou T, Casagrande C, Riboli E, Kaaks R (2006). Body mass index, waist circumference and waist-hip ratio and serum levels of IGF-I and IGFBP-3 in European women. Int J Obes (Lond); 30(11):1623-1631. Henderson KD, Rinaldi S, Kaaks R, Kolonel L, Henderson B, Le Marchand L (2007). Lifestyle

and Dietary Correlates of Plasma Insulin-Like Growth Factor Binding Protein-1 (IGFBP-1), Leptin, and C-Peptide: The Multiethnic Cohort. Nutr Cancer; 58(2):136-145. Hunt KJ, Lukanova A, Rinaldi S, Lundin E, Norat T, Palmqvist R, Stattin P, Riboli E, Hallmans G, Kaaks R (2006). A potential inverse association between insulin-like growth factor I and hypertension in a cross-sectional study. Ann Epidemiol; 16(7):563-571. Jakszyn P, Bingham S, Pera G, Agudo A, Luben R, Welch A, Boeing H, Del Giudice G, Palli D, Saieva C, Krogh V, Sacerdote C, Tumino R, Panico S, Berglund G, Siman H, Hallmans G, Sanchez MJ, Larranaga N, Barricarte A, Chirlaque MD, Quiros JR, Key TJ, Allen N, Lund E, Carneiro F, Linseisen J, Nagel G, Overvad K, Tjonneland A, Olsen A, Bueno-deMesquita HB, Ocke MO, Peeters PH, Numans ME, Clavel-Chapelon F, Trichopoulou A, Fenger C, Stenling R, Ferrari P, Jenab M, Norat T, Riboli E, Gonzalez CA (2006). Endogenous versus exogenous exposure to N-nitroso compounds and gastric cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST) study. Carcinogenesis; 27(7):1497-1501. Jenab M, Riboli E, Cleveland RJ, Norat T, Rinaldi S, Nieters A, Biessy C, Tjonneland A, Olsen A, Overvad K, Gronbaek H, ClavelChapelon F, Boutron-Ruault MC, Linseisen J, Boeing H, Pischon T, Trichopoulos D, Oikonomou E, Trichopoulou A, Panico S, Vineis P, Berrino F, Tumino R, Masala G, Peters PH, van Gils CH, Bueno-de-Mesquita HB, Ocke MC, Lund E, Mendez MA, Tormo MJ, Barricarte A, Martinez-Garcia C, Dorronsoro M, Quiros JR, Hallmans G, Palmqvist R, Berglund G, Manjer J, Key T, Allen NE, Bingham S, Khaw KT, Cust A, Kaaks R (2007). Serum C-peptide, IGFBP-1 and IGFBP-2 and risk of colon and rectal cancers in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer. 15;121(2):368-376. Jenab M, Riboli E, Ferrari P, Sabate J, Slimani N, Norat T, Friesen M, Tjonneland A, Olsen A, Overvad K, Boutron-Ruault MC, ClavelChapelon F, Touvier M, Boeing H, Schulz M, Linseisen J, Nagel G, Trichopoulou A, Naska A, Oikonomou E, Krogh V, Panico S, Masala G, Sacerdote C, Tumino R, Peeters PH, Numans ME, Bueno-de-Mesquita HB, Buchner FL, Lund E, Pera G, Sanchez CN, Sanchez MJ, Arriola L, Barricarte A, Quiros JR, Hallmans G, Stenling R, Berglund G, Bingham S, Khaw KT, Key T, Allen N, Carneiro F, Mahlke U, Del Giudice G, Palli D, Kaaks R, Gonzalez CA (2006). Plasma and dietary vitamin C levels and risk of gastric cancer in the European Prospective Investigation into

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Kaaks R, Ferrari P (2006). Dietary intake assessments in epidemiology: can we know what we are measuring? Ann Epidemiol; 16(5):377-380.

Manuguerra M, Matullo G, Veglia F, Autrup H, Dunning AM, Garte S, Gormally E, Malaveille C, Guarrera S, Polidoro S, Saletta F, Peluso M, Airoldi L, Overvad K, RaaschouNielsen O, Clavel-Chapelon F, Linseisen J, Boeing H, Trichopoulos D, Kalandidi A, Palli D, Krogh V, Tumino R, Panico S, Bueno-DeMesquita HB, Peeters PH, Lund E, Pera G, Martinez C, Amiano P, Barricarte A, Tormo MJ, Quiros JR, Berglund G, Janzon L, Jarvholm B, Day NE, Allen NE, Saracci R, Kaaks R, Ferrari P, Riboli E, Vineis P (2007). Multi-factor dimensionality reduction applied to a large prospective investigation on gene-gene and gene-environment interactions. Carcinogenesis; 28(2):414-422. Epub 2006 Sep 6.

Linseisen J, Rohrmann S, Miller AB, Buenode-Mesquita HB, Buchner FL, Vineis P, Agudo A, Gram IT, Janson L, Krogh V, Overvad K, Rasmuson T, Schulz M, Pischon T, Kaaks R, Nieters A, Allen NE, Key TJ, Bingham S, Khaw KT, Amiano P, Barricarte A, Martinez C, Navarro C, Quiros R, Clavel-Chapelon F, Boutron-Ruault MC, Touvier M, Peeters PH, Berglund G, Hallmans G, Lund E, Palli D, Panico S, Tumino R, Tjonneland A, Olsen A, Trichopoulou A, Trichopoulos D, Autier P, Boffetta P, Slimani N, Riboli E (2007). Fruit and vegetable consumption and lung cancer risk: Updated information from the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer. 121(5):11031114. Linseisen J, Rohrmann S, Norat T, Gonzalez CA, Dorronsoro Iraeta M, Morote Gomez P, Chirlaque MD, Pozo BG, Ardanaz E, Mattisson I, Pettersson U, Palmqvist R, Van Guelpen B, Bingham SA, McTaggart A, Spencer EA, Overvad K, Tjonneland A, Stripp C, Clavel-Chapelon F, Kesse E, Boeing H, Klipstein-Grobusch K, Trichopoulou A, Vasilopoulou E, Bellos G, Pala V, Masala G, Tumino R, Sacerdote C, Del Pezzo M, Buenode-Mesquita HB, Ocke MC, Peeters PH, Engeset D, Skeie G, Slimani N, Riboli E (2006). Dietary intake of different types and characteristics of processed meat which might be associated with cancer risk—results from the 24hour diet recalls in the European Prospective Investigation into Cancer and Nutrition (EPIC). Public Health Nutr; 9(4):449-464. Lukanova A, Bjor O, Kaaks R, Lenner P, Lindahl B, Hallmans G, Stattin P (2006). Body mass index and cancer: results from the Northern Sweden Health and Disease Cohort. Int J Cancer; 15;118(2):458-466. Ma M, Pera G, Agudo A, Bueno-de-Mesquita HB, Palli D, Boeing H, Carneiro F, Berrino F, Sacerdote C, Tumino R, Panico S, Berglund G, Manjer J, Johansson I, Stenling R, Martinez C, Dorronsoro M, Barricarte A, Tormo MJ, Quiros JR, Allen N, Key TJ, Bingham S, Linseisen J, Kaaks R, Overvad K, Jensen M, Olsen A, Tjonneland A, Peeters PH, Numans ME, Ocke MC, Clavel-Chapelon F, BoutronRuault MC, Trichopoulou A, Lund E, Slimani N, Jenab M, Ferrari P, Riboli E, Gonzalez CA. (2007). Cereal fiber intake may reduce risk of gastric adenocarcinomas: The EPICEURGAST study. Int J Cancer.; [Epub ahead

Maskarinec G, Takata Y, Chen Z, Gram IT, Nagata C, Pagano I, Hayashi K, Arendell L, Skeie G, Rinaldi S, Kaaks R (2007) .IGF-I and mammographic density in four geographic locations: A pooled analysis. Int J Cancer; 22; [Epub ahead of print] PMID: 17520679 [PubMed - as supplied by publisher]. McKay JD, Kaaks R, Johansson M, Biessy C, Wiklund F, Balter K, Adami HO, Boillot C, Gioia-Patricola L, Canzian F, Stattin P, Gronberg H (2007). Haplotype-based analysis of common variation in the growth hormone receptor gene and prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 16(1):169-173. Moskal A, Norat T, Ferrari P, Riboli E (2007) Alcohol intake and colorectal cancer risk: a dose-response meta-analysis of published cohort studies. Int J Cancer;1;120(3):664-671. Nagel G, Linseisen J, Boshuizen HC, Pera G, Del Giudice G, Westert GP, Bueno-deMesquita HB, Allen NE, Key TJ, Numans ME, Peeters PH, Sieri S, Siman H, Berglund G, Hallmans G, Stenling R, Martinez C, Arriola L, Barricarte A, Chirlaque MD, Quiros JR, Vineis P, Masala G, Palli D, Panico S, Tumino R, Bingham S, Boeing H, Bergmann MM, Overvad K, Boutron-Ruault MC, ClavelChapelon F, Olsen A, Tjonneland A, Trichopoulou A, Bamia C, Soukara S, Sabourin JC, Carneiro F, Slimani N, Jenab M, Norat T, Riboli E, Gonzalez CA (2007). Socioeconomic position and the risk of gastric and oesophageal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST). Int J Epidemiol; 36(1):66-76. Norat T, Dossus L, Rinaldi S, Overvad K, Gronbaek H, Tjonneland A, Olsen A, ClavelChapelon F, Boutron-Ruault MC, Boeing H, Lahmann PH, Linseisen J, Nagel G, Trichopoulou A, Trichopoulos D, Kalapothaki V, Sieri S, Palli D, Panico S, Tumino R, Sacerdote C, Bueno-de-Mesquita HB, Peeters

PH, van Gils CH, Agudo A, Amiano P, Ardanoz E, Martinez C, Quiros R, Tormo MJ, Bingham S, Key TJ, Allen NE, Ferrari P, Slimani N, Riboli E, Kaaks R (2007). Diet, serum insulin-like growth factor-I and IGFbinding protein-3 in European women. Eur J Clin Nutr; 61(1):91-98. Orfanos P, Naska A, Trichopoulos D, Slimani N, Ferrari P, van Bakel M, Deharveng G, Overvad K, Tjonneland A, Halkjaer J, Santucci de Magistris M, Tumino R, Pala V, Sacerdote C, Masala G, Skeie G, Engeset D, Lund E, Jakszyn P, Barricarte A, Chirlaque MD, Martinez-Garcia C, Amiano P, Quiros JR, Bingham S, Welch A, Spencer EA, Key TJ, Rohrmann S, Linseisen J, Ray J, Boeing H, Peeters PH, Bueno-de-Mesquita HB, Ocke M, Johansson I, Johansson G, Berglund G, Manjer J, Boutron-Ruault MC, Touvier M, ClavelChapelon F, Trichopoulou A (2007). Eating out of home and its correlates in 10 European countries. The European Prospective Investigation into Cancer and Nutrition (EPIC) study. Public Health Nutr; 21:1-11. Palli D, Masala G, Del Giudice G, Plebani M, Basso D, Berti D, E Numans M, Ceroti M, Peeters PH, de Mesquita HB, Buchner FL, Clavel-Chapelon F, Boutron-Ruault MC, Krogh V, Saieva C, Vineis P, Panico S, Tumino R, Nyren O, Siman H, Berglund G, Hallmans G, Sanchez MJ, Larranaga N, Barricarte A, Navarro C, Quiros JR, Key T, Allen N, Bingham S, Khaw KT, Boeing H, Weikert C, Linseisen J, Nagel G, Overvad K, Thomsen RW, Tjonneland A, Olsen A, Trichoupoulou A, Trichopoulos D, Arvaniti A, Pera G, Kaaks R, Jenab M, Ferrari P, Nesi G, Carneiro F, Riboli E, Gonzalez CA (2007). CagA+ Helicobacter pylori infection and gastric cancer risk in the EPIC-EURGAST study. Int J Cancer; 15;120(4):859-867. Peeters PH, Slimani N, van der Schouw YT, Grace PB, Navarro C, Tjonneland A, Olsen A, Clavel-Chapelon F, Touillaud M, BoutronRuault MC, Jenab M, Kaaks R, Linseisen J, Trichopoulou A, Trichopoulos D, Dilis V, Boeing H, Weikert C, Overvad K, Pala V, Palli D, Panico S, Tumino R, Vineis P, Bueno-deMesquita HB, van Gils CH, Skeie G, Jakszyn P, Hallmans G, Berglund G, Key TJ, Travis R, Riboli E, Bingham SA. (2007). Variations in plasma phytoestrogen concentrations in European adults. J Nutr; 137(5):1294-1300. Peeters PH, Lukanova A, Allen N, Berrino F, Key T, Dossus L, Rinaldi S, van Gils CH, Bueno-de-Mesquita HB, Boeing H, Schulz M, Chang-Claude J, Linseisen J, Panico S, Sacerdote C, Palli D, Tumino R, Trichopoulou A, Trichopolos D, Bamia C, Larranaga N, Ardanaz E, Pera G, Quiros JR, Martinez-Garcia C, Navarro C, Bingham SA, Khaw KT, Clavel F, 9

Biostatistics and Epidemiology Cluster Tjonneland A, Olsen A, Overvad K, Tetsche MS, Lund E, Lundin E, Berglund G, Riboli E, Kaaks R (2007). Serum IGF-I, its major binding protein (IGFBP-3) and epithelial ovarian cancer risk: the European Prospective Investigation into Cancer and Nutrition (EPIC). Endocr Relat Cancer; 14(1):81-90.

Agren A, Berglund G, Manjer J, Kumle M, Lund E, Slimani N, Saracci R, Riboli E, Kaaks R (2007). Endogenous androgens and risk of epithelial ovarian cancer: results from the European Prospective Investigation into Cancer and Nutrition (EPIC). Cancer Epidemiol Biomarkers Prev; 16(1):23-29.

Pischon T, Lahmann PH, Boeing H, Friedenreich C, Norat T, Tjonneland A, Halkjaer J, Overvad K, Clavel-Chapelon F, BoutronRuault MC, Guernec G, Bergmann MM, Linseisen J, Becker N, Trichopoulou A, Trichopoulos D, Sieri S, Palli D, Tumino R, Vineis P, Panico S, Peeters PH, Bueno-deMesquita HB, Boshuizen HC, Van Guelpen B, Palmqvist R, Berglund G, Gonzalez CA, Dorronsoro M, Barricarte A, Navarro C, Martinez C, Quiros JR, Roddam A, Allen N, Bingham S, Khaw KT, Ferrari P, Kaaks R, Slimani N, Riboli E (2006). Body size and risk of colon and rectal cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC). J Natl Cancer Inst; 5;98(13):920-931.

Rinaldi S, Key TJ, Peeters PH, Lahmann PH, Lukanova A, Dossus L, Biessy C, Vineis P, Sacerdote C, Berrino F, Panico S, Tumino R, Palli D, Nagel G, Linseisen J, Boeing H, Roddam A, Bingham S, Khaw KT, Chloptios J, Trichopoulou A, Trichopoulos D, Tehard B, Clavel-Chapelon F, Gonzalez CA, Larranaga N, Barricarte A, Quiros JR, Chirlaque MD, Martinez C, Monninkhof E, Grobbee DE, Bueno-de-Mesquita HB, Ferrari P, Slimani N, Riboli E, Kaaks R (2006). Anthropometric measures, endogenous sex steroids and breast cancer risk in postmenopausal women: a study within the EPIC cohort. Int J Cancer; 1;118(11):2832-2839.

Pischon T, Lahmann PH, Boeing H, Tjonneland A, Halkjaer J, Overvad K, Klipstein-Grobusch K, Linseisen J, Becker N, Trichopoulou A, Benetou V, Trichopoulos D, Sieri S, Palli D, Tumino R, Vineis P, Panico S, Monninkhof E, Peeters PH, Bueno-deMesquita HB, Buchner FL, Ljungberg B, Hallmans G, Berglund G, Gonzalez CA, Dorronsoro M, Gurrea AB, Navarro C, Martinez C, Quiros JR, Roddam A, Allen N, Bingham S, Khaw KT, Kaaks R, Norat T, Slimani N, Riboli E. (2006). Body size and risk of renal cell carcinoma in the European Prospective Investigation into Cancer and Nutrition (EPIC).Int J Cancer;118(3):728-738. Reeves GK, Kan SW, Key T, Tjonneland A, Olsen A, Overvad K, Peeters PH, ClavelChapelon F, Paoletti X, Berrino F, Krogh V, Palli D, Tumino R, Panico S, Vineis P, Gonzalez CA, Ardanaz E, Martinez C, Amiano P, Quiros JR, Tormo MR, Khaw KT, Trichopoulou A, Psaltopoulou T, Kalapothaki V, Nagel G, Chang-Claude J, Boeing H, Lahmann PH, Wirfalt E, Kaaks R, Riboli E. (2006). Breast cancer risk in relation to abortion: Results from the EPIC study. Int J Cancer; 1;119(7):1741-1745. Rinaldi S, Dossus L, Lukanova A, Peeters PH, Allen NE, Key T, Bingham S, Khaw KT, Trichopoulos D, Trichopoulou A, Oikonomou E, Pera G, Larranaga N, Martinez-Garcia C, Ardanaz E, Quiros JR, Tormo MJ, Tjonneland A, Olsen A, Overvad K, Chang-Claude J, Linseisen J, Schulz M, Boeing H, van Gils CH, Bueno-de-Mesquita BH, Pala V, Palli D, Panico S, Tumino R, Vineis P, Clavel-Chapelon F, Mesrine S, Boutron-Ruault MC, Lundin E, 10

Rinaldi S, Peeters PH, Bezemer ID, Dossus L, Biessy C, Sacerdote C, Berrino F, Panico S, Palli D, Tumino R, Khaw KT, Bingham S, Allen NE, Key T, Jensen MK, Overvad K, Olsen A, Tjonneland A, Amiano P, Ardanaz E, Agudo A, Martinez-Garcia C, Quiros JR, Tormo MJ, Nagel G, Linseisen J, Boeing H, Schulz M, Grobbee DE, Bueno-de-Mesquita HB, Koliva M, Kyriazi G, Thrichopoulou A, Boutron-Ruault MC, Clavel-Chapelon F, Ferrari P, Slimani N, Saracci R, Riboli E, Kaaks R (2006). Relationship of alcohol intake and sex steroid concentrations in blood in pre- and post-menopausal women: the European Prospective Investigation into Cancer and Nutrition. Cancer Causes Control; 17(8):1033-1043. Rinaldi S, Peeters PH, Berrino F, Dossus L, Biessy C, Olsen A, Tjonneland A, Overvad K, Clavel-Chapelon F, Boutron-Ruault MC, Tehard B, Nagel G, Linseisen J, Boeing H, Lahmann PH, Trichopoulou A, Trichopoulos D, Koliva M, Palli D, Panico S, Tumino R, Sacerdote C, van Gils CH, van Noord P, Grobbee DE, Bueno-de-Mesquita HB, Gonzalez CA, Agudo A, Chirlaque MD, Barricarte A, Larranaga N, Quiros JR, Bingham S, Khaw KT, Key T, Allen NE, Lukanova A, Slimani N, Saracci R, Riboli E, Kaaks R (2006). IGF-I, IGFBP-3 and breast cancer risk in women: The European Prospective Investigation into Cancer and Nutrition (EPIC). Endocr Relat Cancer; 13(2):593-605. Rohrmann S, Becker N, Linseisen J, Nieters A, Rudiger T, Raaschou-Nielsen O, Tjonneland A, Johnsen HE, Overvad K, Kaaks R, Bergmann MM, Boeing H, Benetou V, Psaltopoulou T, Trichopoulou A, Masala G, Mattiello A, Krogh V, Tumino R, van Gils CH, Peeters PH, Bueno-de-Mesquita HB, Ros MM, Lund E,

Ardanaz E, Chirlaque MD, Jakszyn P, Larranaga N, Losada A, Martinez-Garcia C, Agren A, Hallmans G, Berglund G, Manjer J, Allen NE, Key TJ, Bingham S, Khaw KT, Slimani N, Ferrari P, Boffetta P, Norat T, Vineis P, Riboli E (2007). Fruit and vegetable consumption and lymphoma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cancer Causes Control; 18(5):537-549. Rohrmann S, Linseisen J, Boshuizen HC, Whittaker J, Agudo A, Vineis P, Boffetta P, Jensen MK, Olsen A, Overvad K, Tjonneland A, Boutron-Ruault MC, Clavel-Chapelon F, Bergmann MM, Boeing H, Allen N, Key T, Bingham S, Khaw KT, Kyriazi G, Soukara S, Trichopoulou A, Panico S, Palli D, Sieri S, Tumino R, Peeters PH, Bueno-de-Mesquita HB, Buchner FL, Gram IT, Lund E, Ardanaz E, Chirlaque MD, Dorronsoro M, Perez MJ, Quiros JR, Berglund G, Janzon L, Rasmuson T, Weinehall L, Ferrari P, Jenab M, Norat T, Riboli E (2006). Ethanol intake and risk of lung cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). Am J Epidemiol. 1;164(11):1103-1114. Schulz M, Nothlings U, Allen N, OnlandMoret NC, Agnoli C, Engeset D, Galasso R, Wirfalt E, Tjonneland A, Olsen A, Overvad K, Boutron-Ruault MC, Chajes V, ClavelChapelon F, Ray J, Hoffmann K, Chang-Claude J, Kaaks R, Trichopoulos D, Georgila C, Zourna P, Palli D, Berrino F, Tumino R, Vineis P, Panico S, Bueno-deMesquita HB, Ocke MC, Peeters PH, Lund E, Gram IT, Skeie G, Berglund G, Lundin E, Hallmans G, Gonzalez CA, Quiros JR, Dorronsoro M, Martinez C, Tormo MJ, Barricarte A, Bingham S, Khaw KT, Key TJ, Jenab M, Rinaldi S, Slimani N, Riboli E ( 2007). No association of consumption of animal foods with risk of ovarian cancer. Cancer Epidemiol Biomarkers Prev; 16(4):852-855. Sinilnikova OM, McKay JD, Tavtigian SV, Canzian F, DeSilva D, Biessy C, Monnier S, Dossus L, Boillot C, Gioia L, Hughes DJ, Jensen MK, Overvad K, Tjonneland A, Olsen A, Clavel-Chapelon F, Chajes V, Joulin V, Linseisen J, Chang-Claude J, Boeing H, Dahm S, Trichopoulou A, Trichopoulos D, Koliva M, Khaw KT, Bingham S, Allen NE, Key T, Palli D, Panico S, Berrino F, Tumino R, Vineis P, Bueno-de-Mesquita HB, Peeters PH, van Gils CH, Lund E, Pera G, Quiros JR, Dorronsoro M, Martinez Garcia C, Tormo MJ, Ardanaz E, Hallmans G, Lenner P, Berglund G, Manjer J, Riboli E, Lenoir GM, Kaaks R (2007).Haplotype-based analysis of common variation in the acetyl-coA carboxylase alpha gene and breast cancer risk: a case-control study nested within the European Prospective

Epidemiology Methods and Support Group Investigation into Cancer and Nutrition. Cancer Epidemiol Biomarkers Prev; 16(3):409-415. Slimani N, Deharveng G, Unwin I, Southgate DA, Vignat J, Skeie G, Salvini S, Parpinel M, Moller A, Ireland J, Becker W, Farran A, Westenbrink S, Vasilopoulou E, Unwin J, Borgejordet A, Rohrmann S, Church S, Gnagnarella P, Casagrande C, van Bakel M, Niravong M, Boutron-Ruault MC, Stripp C, Tjonneland A, Trichopoulou A, Georga K, Nilsson S, Mattisson I, Ray J, Boeing H, Ocke M, Peeters PH, Jakszyn P, Amiano P, Engeset D, Lund E, Santucci de Magistris M, Sacerdote C, Welch A, Bingham S, Subar AF, Riboli E (2007). The EPIC nutrient database project (ENDB): a first attempt to standardize nutrient databases across the 10 European countries participating in the EPIC study. Eur J Clin Nutr;. 21; [Epub ahead of print] PMID: 17375121 [PubMed - as supplied by publisher]. Stattin P, Bjor O, Ferrari P, Lukanova A, Lenner P, Lindahl B, Hallmans G, Kaaks R (2007). Prospective study of hyperglycemia and cancer risk. Diabetes Care; 30(3):561-567. Steindorf K, Friedenreich C, Linseisen J, Rohrmann S, Rundle A, Veglia F, Vineis P, Johnsen NF, Tjonneland A, Overvad K, Raaschou-Nielsen O, Clavel-Chapelon F, Boutron-Ruault MC, Schulz M, Boeing H, Trichopoulou A, Kalapothaki V, Koliva M, Krogh V, Palli D, Tumino R, Panico S, Monninkhof E, Peeters PH, Boshuizen HC, Buenode-Mesquita HB, Chirlaque MD, Agudo A, Larranaga N, Quiros JR, Martinez C, Barricarte A, Janzon L, Berglund G, Bingham S, Khaw KT, Key TJ, Norat T, Jenab M, Cust A, Riboli E (2006).Physical activity and lung cancer risk in the European Prospective Investigation into Cancer and Nutrition Cohort. Int J Cancer; 15;119(10):2389-2397. Stocks T, Lukanova A, Rinaldi S, Biessy C, Dossus L, Lindahl B, Hallmans G, Kaaks R, Stattin P (2007). Insulin resistance is inversely related to prostate cancer: a prospective study in Northern Sweden. Int J Cancer; 15;120(12):2678-2686. Takata Y, Maskarinec G, Rinaldi S, Kaaks R, Nagata C (2006). Serum insulin-like growth factor-I levels among women in Hawaii and Japan with different levels of tofu intake. Nutr Cancer; 56(2):136-142. Tjonneland A, Christensen J, Olsen A, Stripp C, Thomsen BL, Overvad K, Peeters PH, van Gils CH, Bueno-de-Mesquita HB, Ocke MC, Thiebaut A, Fournier A, Clavel-Chapelon F, Berrino F, Palli D, Tumino R, Panico S, Vineis P, Agudo A, Ardanaz E, Martinez-Garcia C, Amiano P, Navarro C, Quiros JR, Key TJ, Reeves G, Khaw KT, Bingham S, Trichopoulou

A, Trichopoulos D, Naska A, Nagel G, ChangClaude J, Boeing H, Lahmann PH, Manjer J, Wirfalt E, Hallmans G, Johansson I, Lund E, Skeie G, Hjartaker A, Ferrari P, Slimani N, Kaaks R, Riboli E (2007). Alcohol intake and breast cancer risk: the European Prospective Investigation into Cancer and Nutrition (EPIC). Cancer Causes Control; 18(4):361-373. Travis RC, Key TJ, Allen NE, Appleby PN, Roddam AW, Rinaldi S, Egevad L, Gann PH, Rohrmann S, Linseisen J, Pischon T, Boeing H, Johnsen NF, Tjonneland A, Overvad K, Kiemeney L, Bueno-de-Mesquita HB, Bingham S, Khaw KT, Tumino R, Sieri S, Vineis P, Palli D, Quiros JR, Ardanaz E, Chirlaque MD, Larranaga N, Gonzalez C, Sanchez MJ, Trichopoulou A, Bikou C, Trichopoulos D, Stattin P, Jenab M, Ferrari P, Slimani N, Riboli E, Kaaks R (2007). Serum androgens and prostate cancer among 643 cases and 643 controls in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer. 2007 May 18; [Epub ahead of print] PMID: 17514649 [PubMed - as supplied by publisher]. Verheus M, Peeters PH, Rinaldi S, Dossus L, Biessy C, Olsen A, Tjonneland A, Overvad K, Jeppesen M, Clavel-Chapelon F, Tehard B, Nagel G, Linseisen J, Boeing H, Lahmann PH, Arvaniti A, Psaltopoulou T, Trichopoulou A, Palli D, Tumino R, Panico S, Sacerdote C, Sieri S, van Gils CH, Bueno-de-Mesquita BH, Gonzalez CA, Ardanaz E, Larranaga N, Garcia CM, Navarro C, Quiros JR, Key T, Allen N, Bingham S, Khaw KT, Slimani N, Riboli E, Kaaks R (2006). Serum C-peptide levels and breast cancer risk: results from the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer; 1;119(3):659667. Vineis P, Hoek G, Krzyzanowski M, VignaTaglianti F, Veglia F, Airoldi L, Autrup H, Dunning A, Garte S, Hainaut P, Malaveille C, Matullo G, Overvad K, Raaschou-Nielsen O, Clavel-Chapelon F, Linseisen J, Boeing H, Trichopoulou A, Palli D, Peluso M, Krogh V, Tumino R, Panico S, Bueno-De-Mesquita HB, Peeters PH, Lund EE, Gonzalez CA, Martinez C, Dorronsoro M, Barricarte A, Cirera L, Quiros JR, Berglund G, Forsberg B, Day NE, Key TJ, Saracci R, Kaaks R, Riboli E (2006). Air pollution and risk of lung cancer in a prospective study in Europe. Int J Cancer; 1;119(1):169-174. Waijers PM, Ocke MC, van Rossum CT, Peeters PH, Bamia C, Chloptsios Y, van der Schouw YT, Slimani N, Bueno-de-Mesquita HB (2006). Dietary patterns and survival in older Dutch women. Am J Clin Nutr; 83(5):1170-1176.

Weikert S, Boeing H, Pischon T, Olsen A, Tjonneland A, Overvad K, Becker N, Linseisen J, Lahmann PH, Arvaniti A, Kassapa C, Trichoupoulou A, Sieri S, Palli D, Tumino R, Vineis P, Panico S, van Gils CH, Peeters PH, Bueno-de-Mesquita HB, Buchner FL, Ljungberg B, Hallmans G, Berglund G, Wirfalt E, Pera G, Dorronsoro M, Gurrea AB, Navarro C, Martinez C, Quiros JR, Allen N, Roddam A, Bingham S, Jenab M, Slimani N, Norat T, Riboli E (2006). Fruits and vegetables and renal cell carcinoma: findings from the European prospective investigation into cancer and nutrition (EPIC). Int J Cancer; 15;118(12):3133-3139. Weiss JM, Huang WY, Rinaldi S, Fears TR, Chatterjee N, Chia D, Crawford ED, Kaaks R, Hayes RB (2007). IGF-1 and IGFBP-3: Risk of prostate cancer among men in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Int J Cancer. 27; [Epub ahead of print] Wiren S, Stocks T, Rinaldi S, Hallmans G, Bergh A, Stenman UH, Kaaks R, Stattin P (2007). Androgens and prostate cancer risk: A prospective study. Prostate 1;67(11):12301237. Zeleniuch-Jacquotte A, Lundin E, Micheli A, Koenig KL, Lenner P, Muti P, Shore RE, Johansson I, Krogh V, Lukanova A, Stattin P, Afanasyeva Y, Rinaldi S, Arslan AA, Kaaks R, Berrino F, Hallmans G, Toniolo P, Adlercreutz H (2006). Circulating enterolactone and risk of endometrial cancer. Int J Cancer; 15;119(10):2376-2381.

Books (written and edited) IARC Working group on risk of skin cancer and exposure to artificial light, Autier P, Boniol M, Boyle P, Daniel J, Dore JF, Gandini S, Green A, Newton-Bishop J, Weinstock MA, Westerdahl J, Secretan B, Walter SD. Exposure to artificial UV radiation and skin cancer. IARC Working Group Reports Volume 1, Lyon, 2006, IARC.

Book Chapters Boniol M, Doré JF, Autier P, Smans M, Boyle P. Descriptive epidemiology of skin cancer incidence and mortality. pp. 203-223 In Skin Cancer Prevention, Ringborg U, Brandberg Y, Breitbart EW, Greinert R, eds., Informa healthcare 2007. Doré JF, Boniol M, Chignol MC, Autier P. The usefulness of sunscreens. pp. 241-278 In Skin Cancer Prevention, Ringborg U, Brandberg Y, Breitbart EW, Greinert R, eds., Informa healthcare 2007.

11

Data Analysis and Interpretation Group (DEA)

Head Dr Hai-Rim Shin (since July 2007) Dr Philippe Autier (Head between March 2006 and January 2007, acting between January 2007 and July 2007) Scientists Dr Eva Steliarova-Foucher (from March 2006) Visiting scientists Dr Jean-Pierre Boissel (from July 2006)

The DEA Group, created in the spring of 2006, has the objective to make the best use of all existing descriptive epidemiology data to develop better hypotheses on the etiology of cancer, to report on the development of prevention and screening activities and efficacy of treatments. The overall objective of the Group is to develop a comprehensive program of activities on the creation of appropriate statistical methodology for the analysis of descriptive epidemiology data; to apply statistical methods to the analysis of available incidence and mortality data; to provide assistance in data analysis to Cancer Registries and Vital Statistics Offices worldwide; to provide interpretation of the available data and the data analyses for the development of priority hypotheses, and finally to work with appropriate Teams and Groups within IARC and external bodies to develop and undertake appropriate etiological studies. One of the major projects of the Group during this biennium was the EC-funded Eurocan+Plus Project, initiated to propose a solution to the problem of fragmentation and lack of sustainability in the cancer research domain. Eurocan+Plus, which 12

Prof Jean-François Doré Dr Sara Gandini Dr Jan Alvar Lindencrona (from July 2006)

Students Mr Driss Ait Ouakrim (between May 2006 and August 2007) Ms Clarisse Hery (from March 2006)

Informatics Officer Mr Jacques Ferlay (from March 2006)

Consultant Prof Gordon McVie

Assistants Mr Eric Masuyer (from March 2006) Mrs Aurélie Millerat (from January 2007)

Secretary Mrs Elsa Labrosse (from July 2006 until June 2007)

involves almost 300 participants throughout the EU and seeks the views of all stakeholders in the cancer research community, is designed to identify barriers to collaboration in research and recommend methods of overcoming these hurdles to improve cancer research in Europe. Achieving this goal will bring about real progress in cancer control and allow Europe to move beyond what is currently possible within our current knowledge situation. It will also have positive effects on the efficient use of resources, quality of cancer research, quality of patient care, the attractiveness of Europe for the biomedical industry and the organisation of education for doctors and researchers. The Project has identified the main barriers to collaboration and the areas that would most benefit from coordination and believes that the best way to overcome these barriers is the formation of a light but permanent European Cancer Initiative, which will mainly serve to do the following:

3) Manage networks active in cancer research, 4) Give guidance for translational, clinical and epidemiological research, 5) Be a “one-stop shop” as a contact interface with industry, and 6) Arrange targeted funding for projects that need rapid attention.

1) Provide proactive leadership in the cancer research community, 2) Be an information exchange portal,

The European Cancer Initiative will be formed to work with existing structures to monitor, advise, and coordinate European cancer research. The final results of the two years of studies will be presented at the Final General Assembly of the Project in November 2007, and the Project will end at the end of 2007. For more information, and for the results of the investigation when they become available, visit the Project website, www.eurocanplus.eu. This project was transferred to the BIO Group in 2007. The Group is composed of two teams, the Cancer Intelligence Team (CIT) and the Descriptive Epidemiology Analysis Team. The goal of CIT is to describe and interpret cancer incidence and mortality data, in close collaboration with the DEP Group. A specific focus of this team is the

Data Analysis and Interpretation Group

epidemiology of childhood cancer, within several on-going studies. The database of the Automated Childhood Cancer Information System (ACCIS) has been explored in a series of articles on survival of children with cancer, using a novel method of period survival. Looking for causes of childhood cancer is the objective of another study, initially limited to Wilms’ tumour. Finally, the late effects of childhood cancer are studied in collaboration with the team from the childhood cancer registry of Rhône-Alpes. The expertise in the descriptive epidemiology of childhood cancer has also contributed to the international programme My Child Matters, organised by the UICC and devoted to improving the understanding and management of childhood cancer in selected low-resource countries. The Descriptive Epidemiology Analysis Team aims to analyse temporal trends and gather additional descriptive information about these trends to allow a better interpretation of the reasons for temporal changes in incidence and mortality. Thyroid, kidney, bladder and oesophageal cancers have been studied with a special emphasis on Europe. The estimation of the burden of cancer is also an important project for the team, and regular results for Europe (2004 and 2006) have already been published. The

GLOBOCAN estimates will be updated when the data from CI5 Vol. IX are published. A secondary goal is to improve accessibility to and comprehension of this information by the general public. This team works on understanding what the raw statistics mean and turning this information into a format that is clear to the layperson. An Internet-based application has been developed by the group to present the latest incidence data from CI5 Vol. IX. In collaboration with the Association of the Nordic Cancer Registries (ANCR), the NORDCAN web application has been launched (http://www-dep.iarc.fr/NORDCAN.htm). It provides access to the most up-to-date information on the incidence, mortality and prevalence of cancer in the five Nordic countries. This expertise in the data presentation of epidemiological material to a large audience will be used to update the CANCERMondial web site. Another ongoing project of the Group is on the analysis of temporal–spatial trends in breast cancer incidence and mortality. Since 1985, considerable changes have taken place in the early detection and treatment of breast cancer. Description of incidence or mortality trends across a long period of time could give us information on how these changes

may have affected the burden of breast cancer. Initial analyses and trends have been calculated in collaboration with the European Cancer Network and these methods and analyses will be applied to the same kind of study of breast cancer in Asia. The Group also set up a Working Group on UV Radiation, which released a position paper in 2006. Group members have attended different meetings, including PACT (Program of Action for Cancer Therapy) meetings in Viet Nam organized by the IAEA (International Agency for Atomic Energy, Vienna); a Symposium on breast cancer, The Lancet Asia Medical Forum, as well as the 8th Forum for Cancer Control Strategy in Seoul, Korea, the 24th Annual International Papillomavirus Conference in Beijing, the SIOP congress (Geneva 2006), and the French parliamentary meeting ‘Alcohol and Prevention’ (Paris 2006). Since December 2006, DEA has contributed significantly to the activities of the International Association of Cancer Registries (IACR), facilitated by Eva Steliarova-Foucher in the office of Executive Secretary of the Association. The IACR activities are described in more detail in the report of the DEP Group.

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Biostatistics and Epidemiology Cluster

The DEA Group is grateful to the following for their collaboration in its projects: Hermann Brenner (Heidelberg, Germany), Volker Arndt (Heidelberg, Germany), Grazia Valsecchi (Milan, Italy), Charles Stiller (Oxford, UK), Claire Berger (Saint Etienne, France). Financial Support from the following bodies is gratefully acknowledged: The Conseil général du Rhône and the Cancéropôle Lyon Auvergne Rhône-Alpes; Agence Française de Sécurité Sanitaire de l’Environnement et du Travail (AFSSET), Federal Ministry of Health for the German Federal Government.

Publications Arbyn M, Raifu AO, Autier P, Ferlay J (2007). Burden of cervical cancer in Europe: estimates for 2004. Ann Oncol; 18(10):1708-1715. Arndt V, Kaatsch P, Steliarova-Foucher E, Peris-Bonet R, Brenner H. Up-to-date monitoring of childhood cancer long-term survival in Europe: Central nervous system tumours. Ann Oncol; 18: 1734–1742, 2007. Arndt V, Lacour B, Steliarova-Foucher E, Spix C, Znaor A, Pastore G, Stiller CA, Brenner H (2007). Up-to-date monitoring of childhood cancer long-term survival in Europe: Tumours of the sympathetic nervous system, retinoblastoma, renal and bone tumours and soft tissue sarcomas. Ann Oncol; 18: 1722–1733, 2007. Autier P, Gandini S (2007). Vitamin D supplementation and total mortality: A meta-analysis of randomized controlled trials. Ann Oncol; 167:1730-1737. Autier P, Boniol M, Doré JF (2007). Sunscreen use and increased duration of intentional sun exposure: Still a burning issue. Int J Cancer; 121:1-5. Bae J, Gwack J, Park SK, Shin HR, Chang SH, Yoo KY (2007). Cigarette smoking, alcohol consumption, tuberculosis and risk of lung cancer: the Korean multi-center cancer cohort study [Korean]. J Prev Med Pub Health;;40(4):321-8. Bosetti C, Garavello W, Levi F, Ferlay J, Lucchini F, Bertuccio P, Negri E, La Vecchia C (2007). Trends in Oesophageal Cancer Incidence and Mortality in Europe. Int J Cancer; (in press). Bray F, Ferlay J, Devesa SS, McGlynn KA, Møller H (2006). Interpreting the international trends in testicular seminoma and nonseminoma incidence. Nat Clin Pract Urol; 3(10):532543.

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Brenner H, Steliarova-Foucher E, Arndt V (2007). Up-to-date monitoring of childhood cancer long-term survival in Europe: Methodology and application to all forms of cancer combined. Submitted Nov 2006. Ann Oncol; 18: 1561–1568. Brenner H, Coebergh JWW, Parkin DM, Izarzugaza I, Clavel J, Arndt V, SteliarovaFoucher E (2007). Up-to-date monitoring of childhood cancer long-term survival in Europe: Leukaemias and Lymphomas. Ann Oncol; 18: 1569-1577. Cardis E, Krewski D, Boniol M, Drozdovitch V, Darby SC, Gilbert ES, Akiba S, Benichou J, Ferlay J, Gandini S, Hill C, Howe G, Kesminiene A, Moser M, Sanchez M, Storm H, Voisin L, Boyle P (2006). Estimates of the cancer burden in Europe from radioactive fallout from the Chernobyl accident. Int J Cancer; 119(6):1224-1235. Choi Y, Kim Y, Park SK, Shin HR, Yoo KY (2006). Age-period-cohort analysis of female breast cancer mortality in Korea. Breast Cancer; 13(3):266-271. Choo SY, Lee SY, Kim CW, Kim SY, Yoon TH, Shin HR, Moon OR (2007). Educational differences in health care utilization in the last year of life among South Korean cancer patients. J Prev Med Pub Health;40(1):36-44. Korean. Chung HH, Hwang SY, Jung KW, Won YJ, Shin HR, Kim JW, Lee HP (2007). Gynecologic Oncology Committee of Korean Society of Obstetrics and Gynecology. Ovarian cancer incidence and survival in Korea: 1993-2002. Int J Gynecol Cancer; 17(3): 595-600. Clavel J, Steliarova-Foucher E, Berger C, Danon S, Valerianova Z (2006). Hodgkin’s disease incidence and survival in European children and adolescents (1978-1997): report from the ACCIS project Eur J Cancer; 42: 20372049.

Coebergh JWW, Reedijk AMJ, de Vries E, Martos C, Jakab Z, Steliarova-Foucher E, Kamps WA (2006). Leukaemia incidence and survival in children and adolescents in Europe during 1978-1997. Report from the Automated Childhood Cancer Information System project. Eur J Cancer; 42: 2019-2036. de Vries E, Steliarova-Foucher E, Spatz A, Eggermont AMM, Coebergh JWW (2006). Skin cancer incidence and survival in European children and adolescents (1978-1997): report from the ACCIS project. Eur J Cancer; 42: 2170-82. Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P (2007). Cancer Incidence and Mortality in Europe, 2006. Ann Oncol; 16:481-488. Ferlay J, Randi G, Bosetti C, Levi F, Negri E, Boyle P, La Vecchia C (2007). Declining Mortality from Bladder Cancer in Europe. BJU; (in press). Franceschi S, Smith JS, van den Brule A, Herrero R, Arslan A, Anh PT, Xavier Bosch F, Hieu NT, Matos E, Posso H, Qiao YL, Shin HR, Sukvirach S, Thomas JO, Snijders PJ, Munoz N, Meijer CJ (2007). Cervical Infection With Chlamydia trachomatis and Neisseria gonorrhoeae in Women From Ten Areas in Four Continents: A Cross-Sectional Study. Sex Transm Dis; 34(8): 563-569 Franceschi S, Herrero R, Clifford GM, Snijders PJ, Arslan A, Anh PT, Bosch FX, Ferreccio C, Hieu NT, Lazcano-Ponce E, Matos E, Molano M, Qiao YL, Rajkumar R, Ronco G, de Sanjose S, Shin HR, Sukvirach S, Thomas JO, Meijer CJ, Munoz N (2006). Variations in the age-specific curves of human papillomavirus prevalence in women worldwide. Int J Cancer; 119(11):2677-84. Gwack J, Hwang SS, Ko KP, Jun JK, Park SK, Chang SH, Shin HR, Yoo KY (2007). Fasting serum glucose and subsequent liver cancer risk in a Korean prospective cohort. J Prev Med Pub Health; 40(1):23-28. Korean.

Data Analysis and Interpretation Group Gwack J, Shin A, Kim CS, Ko KP, Kim Y, Jun JK, Bae J, Park SK, Hong YC, Kang D, Chang SH, Shin HR, Yoo KY (2006). CagA-producing Helicobacter pylori and increased risk of gastric cancer: a nested case-control study in Korea. Br J Cancer; 95(5):639-641. International Agency for Research on Cancer (2007). Attributable Causes of Cancer in France in the year 2000. Report from an IARC Working Group, Lyon. Izarzugaza MI, Steliarova-Foucher E, Martos C, Zivkovic S (2006). Non-Hodgkin Lymphomas incidence and survival in European children and adolescents (1978-1997): report from the ACCIS project. Eur J Cancer; 42: 2050-2063. Jang SG, Kim IJ, Kang HC, Park HW, Ahn SA, Yoon HJ, Kim K, Shin HR, Lee JS, Park JG (2007). GSTT2 promoter polymorphisms and colorectal cancer risk. BMC Cancer; 25;7:16. Jo H, Jeon YT, Hwang SY, Shin HR, Song YS, Kang SB, Lee HP, Kim JW (2007). Increasing trend in the incidence of cervical cancer among the elderly in Korea: a population-based study from 1993-2002. Acta Oncol; 46 (6): 852-858 Jun JK, Gwack J, Park SK, Choi YH, Kim Y, Shin A, Chang SH, Shin HR, Yoo KY (2006). Fasting serum glucose level and gastric cancer risk in a nested case-control study [Korean]. J Prev Med Pub Health; 39(6):493-498. Jung KW, Yim SH, Kong HJ, Hwang HY, Won YJ, Lee JK, Shin HR (2007). Cancer Survival in Korea 1993-2002: A Population Based Study. JKMS;22(Suppl):S5-10. Kaatsch P, Steliarova-Foucher E, Crocetti E, Magnani C, Spix C, Zambon P (2006). Time trends of cancer incidence in European children (1978-1997): report from the ACCIS project. Eur J Cancer; 42: 1961-1971. Lee JH, Yim SH, Won YJ, Jung KW, Son BO, Lee HD, Lee ES, Yoo KY, Ahn SH, Shin HR, and the members of Korean Breast Cancer Society (KBCS) (2007). Population-based Breast Cancer Statistics in Korea during 1993-2002; incidence, mortality, and survival. JKMS;22(Suppl):S5-10 Lee DH, Liu DY, Jacobs DR Jr, Shin HR, Song K, Lee IK, Kim B, Hider RC (2006). Common presence of non-transferrin-bound iron among patients with type 2 diabetes. Diabetes Care;29(5):1090-1095. Lim MK, Ju YH, Franceschi S, Oh JK, Kong HJ, Hwang SS, Park SK, Cho SI, Sohn WM, Kim DI, Yoo KY, Hong ST, Shin HR (2006). Clonorchis sinensis infection and increasing risk of cholangiocarcinoma in the Republic of

Korea. Am J Trop Med Hyg;75(1):93-96. Magnani C, Pastore G, Coebergh JWW, Viscomi S, Spix C, Steliarova-Foucher E. (2006). Trends in survival after childhood cancer in Europe, 1978-97: the ACCIS project. Eur J Cancer; 42: 1981-2005. MacCarthy A, Draper GJ, Steliarova-Foucher E, Kingston JE (2006). Retinoblastoma incidence and survival in European children (19781997): report from the ACCIS project. Eur J Cancer; 42: 2092-2102. Park SK, Sakoda LC, Kang D, Chokkalingam AP, Lee E, Shin HR, Ahn YO, Shin MH, Lee CW, Lee DH, Blair A, Devesa SS, Hsing AW (2006). Rising prostate cancer rates in South Korea. Prostate; 66(12):1285-1291. Pastore G, Znaor A, Spreafico F, Graf N, Pritchard-Jones K, Steliarova-Foucher E (2006). Malignant renal tumours incidence and survival in European children (1978-1997): report from the ACCIS project. Eur J Cancer; 42: 2103-2114. Pastore G, Peris-Bonet R, Carli M, MartínezGarcía C, Sánchez de Toledo J, SteliarovaFoucher E (2006). Childhood soft tissue sarcomas incidence and survival in European children (1978-97): report from ACCIS project. Eur J Cancer; 42: 2136-2149. Peris-Bonet R, Martínez-García C, Lacour B, Petrovich S, Giner-Ripoll B, Navajas A, Steliarova-Foucher E (2006). Childhood central nervous system tumours. Incidence and survival in Europe (1978-1997): report from the ACCIS project. Eur J Cancer; 42: 206420-80. Pineros M, Ferlay J, Murillo R (2006). Cancer incidence estimates at the national and district levels in Colombia. Salud Publica Mex; 48(6):455-465. Pritchard-Jones K, Kaatsch P, SteliarovaFoucher E, Stiller CA, Coebergh JWW (2006). Cancer in children and adolescents in Europe: Developments over 20 years and future challenges. Eur J Cancer; 42:2183-2190. Sankaranarayanan R and Ferlay J (2006). Worldwide burden of gynaecological cancer: the size of the problem. Best Pract Res Clin Obstet Gynaecol; 20:207-225. Sankila R, Martos Jiménez MC, Miljus D, Pritchard-Jones K, Steliarova-Foucher E, Stiller CA (2006). Geographical comparison of cancer survival in European children (1988-1997): report from the ACCIS project. Eur J Cancer; 42: 1972-1980. Seong MW, Nam MH, Ryu HJ, Kong SY, Myung SK, Seo HG, Shin HR, Park JG, Lee DH (2007). The comparison of two smoking

biomarkers in various biological samples. Clin Chim Acta;383:180-181 Shen C, Kim J, Lee JK, Bae YM, Choi MH, Oh JK, Lim MK, Shin HR, Hong ST (2007). Collection of Clonorchis sinensis adult worms from infected humans after praziquantel treatment. Korean J Parasitol;45(2):149-152. Shin HR (2006). Epidemiology of Hepatitis C Virus in Korea. Intervirology;49:18-22. Shin HR, Park SH, Hwang SY, Kim JE, Jung KW, Won YJ, Hwang SS, Yim SH, Choi KS, Park EC, Park SY, Kim JW, Lee HP (2007). Trends in cervical cancer mortality in Korea 1993-2002: Corrected mortality using national death certification data and national cervical cancer incidence data. IJC; Aug. Spix C, Pastore G, Sankila R, Stiller CA, Steliarova-Foucher E (2006). Neuroblastoma incidence and survival in European children (1978-1997): report from the ACCIS-project. Eur J Cancer; 42: 2081-2091. Stang A, Schmidt-Pokrzywniak A, Lehnert M, Parkin DM, Ferlay J, Bornfeld N, Marr A, Jöckel KH (2006). Population-based incidence estimates of uveal melanoma in Germany. Supplementing cancer registry data by case–control data. Eur Journal Cancer Prev, 15:165–170. Steliarova-Foucher E, Arndt V, Parkin DM, Berrino F, Brenner H (2007). Timely disclosure of progress in childhood cancer survival by period analysis in the Automated Childhood Cancer Information System. Ann Oncol; 18: 1554–1560, 2007. Steliarova-Foucher E (2006). Cancer in the young: the baseline. Eur J Cancer; 42:1697. Steliarova-Foucher E, Kaatsch P, Lacour B, Pompe-Kirn V, Eser S, Miranda A, Danzon A, Ratiu A, Parkin DM (2006). Quality, comparability and methods of analysis of data on childhood cancer in Europe (1978-1997): report from the Automated Childhood Cancer Information System project. Eur J Cancer; 42: 19151951. Steliarova-Foucher E, Stiller CA, Pukkala E, Lacour B, Plesko I, Parkin DM (2006). Thyroid cancer incidence and survival among European children and adolescents (1978-1997): Report from the Automated Childhood Cancer Information System project. Eur J Cancer; 42: 2150-2169. Steliarova-Foucher E, Stiller CA, on behalf of the ACCIS Scientific Committee (2007). The ACCIS (Automated Childhood Cancer Information System) Study. J Pediatr Hematol Oncol; 29:S1-22.

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Biostatistics and Epidemiology Cluster Stiller CA, Marcos-Gragera R, Ardanaz E, Pannelli F, Almar Marqués E, Cañada Martinez A, Steliarova-Foucher E (2006). Geographical patterns of childhood cancer incidence in Europe, 1988-1997: Report from the ACCIS project. Eur J Cancer; 42: 1952-1960. Stiller CA, Desandes E, Danon SE, Izarzugaza MI, Ratiu A, Vassileva-Valerianova Z, Steliarova-Foucher E (2006). Cancer incidence and survival in European adolescents (1978-1997). Report from the ACCIS project. Eur J Cancer; 42: 2006-2018.

from the ACCIS project. Eur J Cancer; 42: 2124-2135. Sung NY, Choi KS, Park EC, Park K, Lee SY, Lee AK, Choi IJ, Jung KW, Won YJ, Shin HR (2007). Smoking, alcohol and gastric cancer risk in Korean men: the National Health Insurance Corporation Study. BJC. July 17

Stiller CA, Pritchard J, Steliarova-Foucher E (2006). Liver cancer in European children: Incidence and Survival, 1978-1997. Report from the ACCIS project. Eur J Cancer; 42: 21152123.

Vaccarella S, Franceschi S, Herrero R, Munoz N, Snijders PJ, Clifford GM, Smith JS, Lazcano-Ponce E, Sukvirach S, Shin HR, de Sanjose S, Molano M, Matos E, Ferreccio C, Anh PT, Thomas JO, Meijer CJ (2006). IARC HPV Prevalence Surveys Study Group. Sexual behavior, condom use, and human papillomavirus: pooled analysis of the IARC human papillomavirus prevalence surveys. Cancer Epidemiol Biomarkers Prev;15(2):326-333.

Stiller CA, Bielack SS, Jundt G, SteliarovaFoucher E (2006). Bone tumours in European children and adolescents, 1978-1997. Report

Vaccarella S, Herrero R, Dai M, Snijders PJ, Meijer CJ, Thomas JO, Hoang Anh PT, Ferreccio C, Matos E, Posso H, de Sanjose S, Shin

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HR, Sukvirach S, Lazcano-Ponce E, Ronco G, Rajkumar R, Qiao YL, Munoz N, Franceschi S (2006). Reproductive Factors, Oral Contraceptive Use, and Human Papillomavirus Infection: Pooled Analysis of the IARC HPV Prevalence Surveys. Cancer Epidemiol Biomarkers Prev;15(11):2148-2153. Yoon KA, Park S, Hwangbo B, Shin HD, Cheong HS, Shin HR, Lee JS (2007). Genetic polymorphisms in the Rb-binding zinc finger gene RIZ and the risk of lung cancer.Carcinogenesis; 28:1971-1977.

Book chapters Steliarova-Foucher E, Hery C, Pisani P. The 10 My Child Matters countries. In: UICC, Childhood Cancer: Rising to the challenge. UICC, Geneva 2006, pp. 9-15

Descriptive Epidemiology Production Group Descriptive Epidemiology Production Group (DEP) Head Dr Paola Pisani (until 30 November 2006) Dr Philippe Autier (acting 1 Dec. 2006–26 April 2007) Dr Maria-Paula Curado (from 27 April 2007) Scientists Mr Jacques Ferlay (until 31 March 2006) Ms Mary Heanue (from 20 April 2006) Dr Eva Steliarova-Foucher (until 31 March 2006) Dr Lydia Voti (from 13 January 2007)

The core activity of the Descriptive Epidemiology Production Group (DEP) is to support cancer registration all over the world and to monitor and provide cancer incidence data as a basis for etiological research and cancer control policies, whether local or international. The information on cancer incidence, mortality, survival and trends quantifies the size of the burden on cancer incidence, making it possible to evaluate cancer control actions taken in that population. We collect cancer incidence statistics through cancer registries, mainly in low- and mediumresource countries, to provide data on the local cancer situation. A crucial issue in these countries is the lack of information on mortality data, so cancer registries really are the most reliable source of information on cancer occurrence. Since 1960, IARC has systematically received data from population-based cancer registries worldwide, which is then refined based on data quality indicators for each cancer registry. The data are subsequently adapted to make comparisons between the populations distributed over the five continents.

Technical Assistants Mr Morten Ervik (from 22 Dec. 2006) Mr Mohssen Issa (27 March-27 August 2006) Mr Eric Masuyer (until 31 March 2006) Mr Mathieu Mazuir (from 12 April 2007) Ms Isabelle Savage (from 8 August 2006) Secretaries Ms Catherine Bénard (from 14 February to 31 August 2006) Ms Chantal Déchaux

Cancer Incidence in Five Continents, Volume IX Editorial Board Meetings were held at IARC on 4–6 July 2006, 11–13 Oct. 2006, 16–19 Jan. 2007, 24–26 April 2007 and 3– 4 July 2007, with the active participation of Drs Maria-Paula Curado, Brenda Edwards, Hans Storm and Hai Rim Shin (see list of collaborators below). The data produced by the populationbased cancer registries have been converted into standardised form and are disseminated to the scientific community. This publication is produced on a 5-year basis, and the current volume is now available through the IARC website. The reference time period was defined to be 1998-2002, and in order to allow the editors to verify some aspects of quality, comparability and completeness, contributors were also asked to send data for the years preceding the reference period. Volume IX is divided into eight chapters: Introduction; Techniques of registration; Classification and coding; Comparability and quality of data: Histological groups; Processing of data;

Ms Evangéline Demourdjian (from 28 Aug. 2006 to 27 Aug. 2007) Ms Susan Haver-Legros (until 31 January 2006) Visiting scientists Dr Cankut Yakut (from 29 Oct. to 30 Nov. 2006) Students Mr Vincent Benoist (from 7 May to 27 July 2007) Ms Marilyne Goutagny (from 7 May to 27 July 2007)

Age standardisation, and Tables. The evaluation criteria used to analyse the data submitted by the cancer registries were based on cancer registration data quality indicators outlined in Cancer Registration, Principles and Methods, IARC Scientific Publication No.95 and the Manual for Cancer Registry Personnel, IARC Technical Report No.10 (Chapter 5). We received data from 406 populations for this volume; we published data on cancer incidence from 300 populations, 225 cancer registries and 60 countries. The proportions of covered cancer registries by continent were: Africa 31.3% (5/16); South and Central America 37.9% (11/29); North America 93.1% (54/58); Asia 57.1% (44/77), Europe 83.3% (100/120); Oceania 84.6% (11/13). The electronic version of the volume is available at www-dep.iarc.fr. The incidence rates and numbers as originally published can be accessed to generate tables and graphs.

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Biostatistics and Epidemiology Cluster

CI(5)/ICD(O)-3 Histological Groups Meeting (16 April 2007) For comparability purposes, data presented in Cancer Incidence in Five Continents (CI5) are mainly classified by site using the International Classification of Diseases (ICD). In Volumes VIII and IX of CI5, chapter II (Neoplasms) headings of ICD10 were the source of the classification. Another axis of interest for cancer is the histological subtypes, and to this end the histological codes have been classified based on the Histological Classification of Tumours according to the ICD-O. IARC Technical Report No.31, Histological Groups for Comparative Studies, was the classification source for volume VIII of CI5. Since then, ICD-O has been updated from Revision 2 to Revision 3, and it has therefore become necessary to update these histological groupings for ICD-O3. With this aim in mind, experts were invited to participate in a pathology panel, the outcome of which is detailed in the publication.

Technical assistance is also provided by Isabelle Savage and Eric Masuyer. This team is responsible for coordinating the activities of the Association and for promoting exchange of information between its almost 600 members all over the world. During the biennium, the IACR Secretariat helped to raise funds and organized two Annual Meetings of the Executive Board: in Goiania, Brazil, 8-10 November 2006, and in Ljubljana, Slovenia, 18-20 September 2007. It also hosted a satellite meeting for the African Region at the AORTIC Conference in November 2007. Other activities included maintenance of the IACR website at http://www.iacr.com.fr/, the publication of the IACR Newsletter, communication with associated journals, management of membership (applications, fees and database) and IACR fellowships. IACR collaborated with IARC in several projects, namely CI5 Volume IX and the development of CanReg, the cancer registry software.

CanReg Software During the biennium, new versions of the CanReg4 software have been developed and installed in Africa (Botswana, Ghana and Nigeria), Latin America (Colombia), Asia (Malaysia, Mongolia, Sri Lanka and Viet Nam), Europe (France and Albania) and Oceania (Cook Islands, Fiji and Niue). Staff were trained during the IARC Annual Summer School in Cancer Epidemiology held in Lyon. A 5th version of the software is currently under preparation.

ENCR (European Network of Cancer Registries) ENCR Steering Committee meetings were held at IARC on 17–18 January 2006, 25–26 April 2006, 12–13 September 2006, 30–31 January 2007, 11–12 April 2007 and 28–29 June 2007. The ENCR also held annual meetings in Palma de Majorca, Spain on 25 May 2006, and in Ljubljana, Slovenia, on 21 September 2007. Members of the Steering Committee include: Freddie Bray (The Cancer Registry of Norway, Oslo), Pascale Grosclaude (Tarn Cancer Registry, Albi, France), Isabel Izarzugaza (Department of Health, Bilbao, Spain), Jean-Michel Lutz (Geneva Tumour Registry and GRELL representative), Henrik Møller (Thames Cancer Registry, London), Hans Storm (Danish Cancer Society and IACR representative) and Laufey Tryggvadottir (Reykjavik Cancer Registry and representative of the Nordic Cancer Registries Association). A grant application has been submitted by the ENCR to the European Commission through its FP7/ERA-Net Programme (Work Package on cancer incidence and trends in Europe). It shows comprehensive and systematic analysis of

IACR/ENCR DEP provides the facilities for the administration and secretariat of the International Association of Cancer Registries (IACR) and the European Network of Cancer Registries (ENCR). IACR (International Association of Cancer Registries) Since 1973, IARC has supported the activities of the non-governmental International Association of Cancer Registries (IACR) by hosting its secretariat. During 2006-07, the role of IACR Executive Secretary was assumed by Dr Paola Pisani until 30 November 2006, and by Eva Steliarova-Foucher since then. 18

time trends in cancer incidence and mortality. The relevance of this subject is related to the prediction of changes in the cancer burden over the time, which may be used to predict future cancer risk and identify new determinants in cancer incidence. A grant proposal covering a collaboration between ENCR and the University of Bielefeld, Germany on the project “Monitoring Health Status of Migrants within Europe: development of indicators” has been submitted to the European Commission. The project aims to identify existing databases with information on ethnic origin and compile definitions of “migrants” as adopted in these sources of information. In addition, it aims to assess the consistency of information on migrants, coverage, completeness and quality of data, and develop recommendations for a uniform definition of the status of migrants for use in cancer registration. Partners in the project are Prof. Alan Krasnick (Denmark) and Prof. Mackenbach (Netherlands). Dr Geppo Costa (Italy) was also suggested. A programme has also been developed to update our SQL-based address-lists available on the web, and our intranet pages have been revised to better suit the needs of the users. Queries were put forward to build tailored address-lists for cancer registries. ACCIS, ECO, EUNICE, EUROCADET, EUROTIS ACCIS Automated Childhood Cancer Information System (ACCIS) is an international project, funded initially by the European Commission and later by several other institutions (La Ligue contre le cancer, Comité du Rhône, Canceropôle Lyon, Auvergne, Rhône-Alpes (CLARA), the Ministry of Health of the Federal Government of Germany) jointly with IARC. This collaborative project of some 80 population-based cancer registries in 35 European countries has risen from the need for substantial population coverage for studies of childhood cancer. To date, basic data have been accumulated for almost 140 000 tumours in patients younger than 15 years at diagnosis, arising

Descriptive Epidemiology Production Group

from 1172 million person-years, and became thus the world’s largest childhood cancer database. The group also participated in the publication of a special issue of the European Journal of Cancer in September 2006, providing the reference data for incidence of and survival from cancer in children and adolescents in Europe, based on the analysis of the ACCIS database, as well as outlook for future epidemiological and clinical research. This work results from collaboration of 78 cancer registries across Europe as data providers and 57 co-authors, including practicing paediatric oncologists. European Cancer Observatory (ECO) The ECO project is supported by the Cancéropôle Lyon, Auvergne, Rhône-Alpes (CLARA), awarded specifically for supporting the activities of the European Network of Cancer Registries (ENCR). This project, outlined in the framework of the epidemiological platform of Cancéropôle includes the following major areas of work: (1) Reinforcement of population-based cancer registration as the only means of measuring the cancer burden in Europe and the basis of etiological studies. (2) Studies of cancer in children that necessitate international collaboration. (3) Scenarios, meaning modelling of the cancer burden in a given population, using available data on incidence, mortality, survival and prevalence. EUNICE The main objectives of the EUNICE project are: (1) to select a core set of indicators to monitor the cancer burden, the intensity of screening for breast, cervix and colorectal cancers, the impact on incidence and mortality of screening for breast and cervix cancers, the availability of radiotherapy facilities by type and patient access to radiotherapy and cancer drugs in the EU member states; (2) to compile a database of the selected indicators for the European countries, and (3) to describe the infrastructure required to obtain those indicators and submit recommendations for countries where data are missing. The project involves IARC, the German Cancer Research Centre Department on Ageing Research in Heidelberg (Prof. H. Brenner), the CPO Piemonte in Turin (Dr

A. Ponti), the Institute of Public Health, Brussels (Prof. M. Arbyn), the Institute for Statistical and Epidemiological Cancer Research, Helsinki (Dr N. Malila), the International Atomic Energy Agency, Vienna (Dr E. Rosenblatt) and the Karolinska Institute, Stockholm (Prof. N. Wilking and Prof. U. Ringborg). EUROCADET The EUROCADET Project, which aims to contribute to the battle against cancer by identifying effective preventive strategies and making estimations of the effects of successful implementation of these strategies, is coordinated by Dr JanWillem Coeberg and Professor Mackenbach from the Erasmus University Medical Centre, Rotterdam on “The Impact of Key Determinants on the Current and Future Burden of Cancer in Europe”. IARC/DEP is a partner in this project. EUROTIS This study, funded by Région RhôneAlpes, was dedicated to the analysis of incidence and mortality trends of thyroid cancer in Europe, with particular emphasis on the histological type in children and adults. A Collaborative Research Agreement was signed between FRANCIM and IARC/DEP, and Dr Marc Colonna, from the Registre des Cancers de l’Isère has taken responsibility for the work, on behalf of FRANCIM. Training (1) Advanced Course on Automated Cancer Registration, Birmingham, 26-27 June 2006 IARC helped in the administrative organisation of this IACR-sponsored course organised by Chris Carrigan (National Coordinator for Cancer Registration in England, National Cancer Action Team, London) and Lorenzo Simonato (University of Padova, Italy). The other members of the faculty included Richard Middleton from Queen’s University, Belfast and Wendy Scharber, from Brooklyn Park, Minnesota, USA. Thirty-nine participants from Austria, Ireland, Italy, Spain, Thailand and the United Kingdom attended that course.

(2) IARC Summer School in Cancer Epidemiology As in previous years, our Group actively participated in the cancer registration modules of the 2006-07 IARC Summer Schools, providing course coordinators (Paola Pisani in 2006 and Mary Heanue in 2007), faculty members and training in cancer registration basic principles, methods in data collection, quality control measures, CanReg software data entry, checks and practical exercises. (3) ENCR Course on Cancer Prediction Methods (IARC, 19-21 Sept 2006) This course was dedicated to the practical aspects of implementing and interpreting cancer predictions as part of a cancer registry’s core activities. Freddie Bray, Bjørn Møller from the Cancer Registry, Oslo, Tadek Dyba and Timo Hakulinen (Course Coordinator) from the Finnish Cancer Registry, and Arduino Verdecchia from ISS, Rome were the faculty representatives. Twenty-nine participants from Austria, Canada, Denmark, France, Germany, Italy, the Netherlands, Poland, Portugal, Romania, Slovenia, Spain, and the United Kingdom participated in the course. Meetings (1) Workshop on Cancer Projections (IARC, 22 Sept 2006) As Freddie Bray, Timo Hakulinen and Tadek Dyba were present in Lyon for the above ENCR course, the opportunity was taken to organise this workshop immediately afterward and to review cancer projection methods. Eric Holowaty (Cancer Care Ontario, Toronto) and Colin Mathers (WHO Global Burden of Disease Programme, Geneva) were the other invited experts. Jacques Ferlay and Paola Pisani (workshop organizer) from IARC also participated. (2) Working Group on Data Production in Low- and Medium-Resource Countries (IARC, 25 July 2007) It was decided to organise this meeting to determine on what basis the Agency would continue supporting cancer registration in the world through its programme of Collaborative Research Agreements. It was considered that the data produced by the registries should be kept 19

Biostatistics and Epidemiology Cluster

independent from CI5 – IARC is doing research to serve the Ministries of Health in different countries, and it should first bear in mind the cancer control/public health activities of these respective countries. Cancer registry data should be seen as an aid to the evaluation of the local cancer burden and as a tool for cancer control. It was decided that IARC would set up a Grant Application Fund for Cancer Registries, to be advertised on the IARC and IACR websites, with all the requisites usually required for grant application purposes. The applications will be reviewed by an official review board nominated by IARC. Collaboration with the IAEA/PACT Programme Dr Mohamed El Baradei, IAEA Director, received the Nobel Prize in 2003, and invested the funds in the setting-up of this Programme of Action for Cancer Therapy in 2004, which will enable developing countries to introduce, expand and improve their cancer care capacity by integrating radiotherapy into a comprehensive cancer control programme

20

that maximizes its therapeutic effectiveness and impact. Pilot countries chosen are Tanzania, Sri Lanka, Viet Nam, Yemen, Nicaragua and Albania. This is a joint effort of WHO, PACT, IARC, INCTR, NCI, UICC, ACS, Tata and other international partners. It should contribute to the initiation of National Cancer Control Plans, increase prevention and early detection programmes, expand palliative programmes, improve and expand radiotherapy services and cancer registration, and go beyond a government’s lifetime. IARC’s contribution to that Programme covers the setting-up of cancer registration at each site. IARC already participated in missions to Albania (2–5 May 2006), Tanzania (29 May–2 June 2006), Viet Nam (30 Oct.–2 Nov. 2006), Yemen (1–5 July 2007), and Nicaragua (23–27 July 2007) and in the development of national cancer control plans in these countries. Collaboration with the UICC “My Child Matters” Programme UICC, in collaboration with SanofiAventis, has established a programme

designed to help improve childhood cancer management in selected low-resource countries. A Selection Advisory Committee consists of the representatives of UICC, St Jude Children's Research Hospital (TN, USA), the International Society of Paediatric Oncology (SIOP), the US National Cancer Institute (NCI), the International Agency for Research on Cancer (IARC), the International Confederation of Childhood Cancer Parent Organisations (ICCCPO), Epidaure CRLC Val d'Aurelle-Paul Lamarque (France), Groupe FrancoAfricain d'Oncologie Pédiatrique, and the International Network for Cancer Treatment and Research (INCTR). The most promising 26 projects in 16 countries were funded, and the programme has been warmly received in the international scientific literature and conferences. IARC has also contributed to the UICC report and a UICC factsheet on childhood cancer for distribution to the general public, published in support of the “My Child Matters” Programme.

Descriptive Epidemiology Production Group

The DEP Group is grateful to the following for their collaboration in its projects: Marc Arbyn, Brussels, Belgium; Freddie Bray, Oslo, Norway; Dan Berney, London, UK; Hermann Brenner, Heidelberg, Germany; Chris Carrigan, London, UK; Jacqueline Clavel, Paris, France; Jan-Willem Coeberg, Rotterdam, The Netherlands; Esther de Vries, Rotterdam, The Netherlands; Tadek Dyba, Helsinki, Finland; Brenda Edwards, Bethesda, MD, USA; Kenneth Fleming, Oxford, UK; April Fritz, Reno, NV, USA; Anna Gavin, Belfast, Ireland; Pascale Grosclaude, Albi, France; Timo Hakulinen, Helsinki, Finland; Joe Harford, Bethesda, MD, USA; Guenter Henze, Berlin, Germany; Eric Holowaty, Toronto, Ontario; Isabel Izarzugaza, San Sebastian, Spain; Peter Kaatsch, Mainz, Germany; Robert Jakob, Geneva, Switzerland; Lars Age Johannson, Stockholm, Sweden; Moussa Koulibaly, Conakry, Guinea; Eduardo Laura, Bahia Blanca, Argentina; Jean-Michel Lutz, Geneva, Switzerland; Angela MacCarthy, Oxford, UK; Corrado Magnani, Turin, Italy; Nea Malila, Helsinki, Finland; Colin Mathers, Geneva, Switzerland; Richard Middleton, Belfast, Ireland; Bjørn Møller, Oslo, Norway; Henrik Møller, London, UK; Guido Pastore, Turin, Italy; Rafael Peris-Bonet, Valencia, Spain; Antonio Ponti, Turin, Italy; Kathy Pritchard-Jones, London, UK; Maja Primic-Zakelj, Ljubljana, Slovenia; Ulrik Ringborg, Stockholm, Sweden; Eduardo Rosenblatt, Vienna, Austria; Risto Sankila, Helsinki, Finland; Wendy Scharber, Brooklyn Park, MN, USA; Hai-Rim Shin, Koyang-si, Republic of Korea; Lorenzo Simonato, Padua, Italy; Claudia Spix, Mainz, Germany; Supanee Sriamporn, Ubonratchathani, Thailand; Charles Stiller, Oxford, UK; Hans Storm, Copenhagen, Denmark; Laufey Tryggvadottir, Reykjavik, Iceland; Arduino Verdecchia, Rome, Italy; Nils Wilking, Stockholm, Sweden; Tongzhang Zhen, New Haven, CT, USA Financial support from the following bodies is gratefully acknowledged: Agence Française de Sécurité Sanitaire de l’ Environnement et du Travail. France (EUROTIS) Cancéropôle Lyon, Auvergne, Rhône-Alpes/CLARA, France (ECO, ACCIS) European Commission (ACCIS, EUROCADET, EUROTIS) German Government (ACCIS) International Union Against Cancer (Childhood Cancer Report) Ligue Nationale contre le Cancer, Comité du Rhône (ACCIS) National Cancer Institute, USA (Cancer registries and CanReg) Région Rhône-Alpes, France (EUROTIS)

Publications Bray F, Ferlay J, Devesa SS, McGlynn KA, Moller H (2006). Interpreting the international trends in testicular seminoma and nonseminoma incidence. Nat Clin Pract Urol; 3(10):532-543. Brem R, Cox DG, Chapot B, Moullan N, Romestaing P, Gerard JP, Pisani P, Hall J (2006). The XRCC1 -77T->C variant: haplotypes, breast cancer risk, response to radiotherapy and the cellular response to DNA damage. Carcinogenesis; 27(12):2469-2474. Clavel J, Steliarova-Foucher E, Berger C, Danon S, Valerianova Z (2006). Hodgkin's disease incidence and survival in European children and adolescents (1978-1997): Report from the Automated Cancer Information System project. Eur J Cancer; 42(13):2037-2049

Coebergh JW, Reedijk AM, De Vries E, Martos C, Jakab Z, Steliarova-Foucher E, Kamps WA (2006). Leukaemia incidence and survival in children and adolescents in Europe during 1978-1997. Report from the Automated Childhood Cancer Information System project. Eur J Cancer; 42(13):2019-2036 De Vries E, Steliarova-Foucher E, Spatz A, Ardanaz E, Eggermont AM, Coebergh JW (2006). Skin cancer incidence and survival in European children and adolescents (19781997). Report from the Automated Childhood Cancer Information System project. Eur J Cancer; 42(13):2170-2182. Izarzugaza MI, Steliarova-Foucher E, Carmen MM, Zivkovic S (2006). Non-Hodgkin's lymphoma incidence and survival in European children and adolescents (1978-1997): Report

from the Automated Childhood Cancer Information System project. Eur J Cancer; 42(13):2050-2063. Kaatsch P, Steliarova-Foucher E, Crocetti E, Magnani C, Spix C, Zambon P (2006). Time trends of cancer incidence in European children (1978-1997): Report from the Automated Childhood Cancer Information System project. Eur J Cancer; 42(13):1961-1971. Maccarthy A, Draper GJ, Steliarova-Foucher E, Kingston JE (2006). Retinoblastoma incidence and survival in European children (1978-1997). Report from the Automated Childhood Cancer Information System project. Eur J Cancer; 42(13):2092-2102. MacKinnon JA, Duncan RC, Huang Y, Lee DJ, Fleming LE, Voti L, Rudolph M, Wilkinson JD.(2007). Detecting an association between 21

Biostatistics and Epidemiology Cluster socio-economic status and late stage breast cancer using spatial analysis and area-based measures. Cancer Epid Biomark Prev;16:756762 Magnani C, Pastore G, Coebergh JW, Viscomi S, Spix C, Steliarova-Foucher E (2006) Trends in survival after childhood cancer in Europe, 1978-1997: Report from the Automated Childhood Cancer Information System project (ACCIS). Eur J Cancer; 42(13):1981-2005. Pastore G, Peris-Bonet R, Carli M, MartinezGarcia C, de Toledo JS, Steliarova-Foucher E (2006). Childhood soft tissue sarcomas incidence and survival in European children (1978-1997): Report from the Automated Childhood Cancer Information System project. Eur J Cancer; 42(13):2136-2149. Pastore G, Znaor A, Spreafico F, Graf N, Pritchard-Jones K, Steliarova-Foucher E (2006). Malignant renal tumours incidence and survival in European children (1978-1997): Report from the Automated Childhood Cancer Information System project. Eur J Cancer; 42(13):2103-2114. Peris-Bonet R, Martinez-Garcia C, Lacour B, Petrovich S, Giner-Ripoll B, Navajas A, Steliarova-Foucher E (2006). Childhood central nervous system tumours - incidence and survival in Europe (1978-1997): Report from Automated Childhood Cancer Information System project. Eur J Cancer; 42(13):2064-2080. Pisani P, Héry C (2006) The burden of childhood cancer. In: UICC Childhood Cancer: Rising to the challenge. UICC, Geneva, pp.9-14. Pisani P, Parkin DM, Ngelangel C, Esteban D, Gibson L, Munson M, Reyes MG, Laudico A (2006). Outcome of screening by clinical examination of the breast in a trial in the Philippines. Int J Cancer; 118(1):149-154. Pisani P, Srivatanakul P, Randerson-Moor J, Vipasrinimit S, Lalitwongsa S, Unpunyo P, Bashir S, Bishop DT (2006) GSTM1 and CYP1A1 polymorphisms, tobacco, air

22

pollution, and lung cancer: a study in rural Thailand. Cancer Epidemiol Biomarkers Prev; 15(4):667-674. Pritchard-Jones K, Kaatsch P, SteliarovaFoucher E, Stiller CA, Coebergh JW (2006) Cancer in children and adolescents in Europe: Developments over 20 years and future challenges. Eur J Cancer; 42(13):2183-2190. Sankaranarayanan R, Ferlay J (2006). Worldwide burden of gynaecological cancer: the size of the problem. Best Pract Res Clin Obstet Gynaecol; 20(2):207-225. Sankila R, Martos Jimenez MC, Miljus D, Pritchard-Jones K, Steliarova-Foucher E, Stiller C (2006). Geographical comparison of cancer survival in European children (1988-1997): Report from the Automated Childhood Cancer Information System project. Eur J Cancer; 42(13):1972-1980. Spix C, Pastore G, Sankila R, Stiller CA, Steliarova-Foucher E (2006). Neuroblastoma incidence and survival in European children (1978-1997): Report from the Automated Childhood Cancer Information System project. Eur J Cancer; 42(13):2081-2091. Stang A, Schmidt-Pokrzywniak A, Lehnert M, Parkin DM, Ferlay J, Bornfeld N, Marr A, Jockel KH (2006). Population-based incidence estimates of uveal melanoma in Germany. Supplementing cancer registry data by case-control data. Eur J Cancer Prev; 15(2):165-170. Steliarova-Foucher E. Héry C, Pisani P. The 10 “My child matters” countries. In: UICC Childhood Cancer: Rising to the challenge, UICC, Geneva, pp.15-30. Steliarova-Foucher E, Coeberg JW, Kaatsch, P. Pritchard-Jones K., Stiller C. Eds. (2006). Cancer in Children and Adolescents in Europe. Eur J Cancer, 42(13):1913-2190. Steliarova-Foucher E, Kaatsch P, Lacour B, Pompe-Kirn V, Eser S, Miranda A, Danzon A, Ratiu A, Parkin DM (2006). Quality,

comparability and methods of analysis of data on childhood cancer in Europe (1978-1997): Report from the Automated Childhood Cancer Information System project. Eur J Cancer; 42(13):1915-1951. Steliarova-Foucher E, Stiller CA, Pukkala E, Lacour B, Plesko I, Parkin DM (2006). Thyroid cancer incidence and survival among European children and adolescents (1978-1997): Report from the Automated Childhood Cancer Information System project. Eur J Cancer; 42(13):2150-2169. Steliarova-Foucher E. Cancer in the young: the baseline. Eur J Cancer; 42(12):1697. Stiller CA, Marcos-Gragera R, Ardanaz E, Pannelli F, Almar ME, Canada MA, Steliarova-Foucher E (2006). Geographical patterns of childhood cancer incidence in Europe, 1988-1997. Report from the Automated Childhood Cancer Information System project. Eur J Cancer; 42(13):19521960. Stiller CA, Desandes E, Danon SE, Izarzugaza I, Ratiu A, Vassileva-Valerianova Z, SteliarovaFoucher E (2006). Cancer incidence and survival in European adolescents (1978-1997). Report from the Automated Childhood Cancer Information System project. Eur J Cancer; 42(13):2006-2018. Stiller CA, Pritchard J, Steliarova-Foucher E. Liver cancer in European children: Incidence and survival, 1978-1997 (2006). Report from the Automated Childhood Cancer Information System project. Eur J Cancer; 42(13):21152123. Stiller CA, Bielack SS, Jundt G, SteliarovaFoucher E. Bone tumours in European children and adolescents, 1978-1997 (2006). Report from the Automated Childhood Cancer Information System project. Eur J Cancer; 42(13):2124-2135.

Information Information Technology Technology Services Services Group Group(ITS) Head Mr Michel Smans Team leader Mr Philippe Damiecki

The Information Technology Services Group (ITS) maintains and develops the Agency’s central computing and electronic communications services. After the organisational changes and physical reorganisation of the last biennium, the Group has put a lot of effort into improving the network (e.g. external bandwidth, security, mail filtering) and the management of our servers (e.g. user administration, backups). A number of improvements have also been brought to the administration tools, whether home grown applications or WHO-HQ provided. In this particular

Technical Assistants Mr Cameron Barnett (from May 2007) Mr Philippe Boutarin Mr Christopher Jack

area, the decision approved by the Governing Council in May 2006 to adopt our own Administration Management System rather than be part of the WHO GSM has led us into a major project in collaboration with the Division of Administration and Finance. The initial study, started in 2006, resulted in SAP being chosen as the basis for the new system. Work began in February 2007 with a definition of the scope of the project and has progressed through training with implementation foreseen for the new biennium of 2008–2009.

Mrs Brigitte Kajo Secretary Ms Laurence Marnat

The collaboration with GCS towards the goal of implementing the new LIMS (Laboratory Information Management System) has been very successful, and the new database is now operational. In collaboration with BIO, a meeting of the European Cancer Mortality Atlas participants was organised in May 2006 to review the material available. The text for the publication is now completed and being edited.

23

Radiation Group (RAD) Head Dr Elisabeth Cardis

Dr Isabelle Thierry-Chef Dr Martine Vrijheid

Secretary Mrs Catherine Chassin

Scientists Dr Isabelle Deltour Dr Vladimir Drozdovitch (until November 2006) Dr Ausrele Kesminiene Mrs Lesley Richardson (until June 2007)

Technical assistants Ms Emilie Combalot (until April 2006) Mrs Monika Moissonnier Ms Marie Sanchez Ms Hélène Tardy Ms Vanessa Tenet

Visiting scientists and postdoctoral fellows Dr Anne-Sophie Evrard

The scope of the work in the Radiation Group (RAD) encompasses both ionising and non-ionising radiation. Ionising radiation is one of the most studied and ubiquitous carcinogens in our general environment. The main basis for radiation protection standards is the study of survivors of the Japanese atomic bomb, a population exposed primarily at high dose-rates. The primary public health concern, however, is the protection of people from relatively low-dose, protracted or fractionated exposures such as those received by the public in the general

environment, by patients through repeated diagnostic procedures, and by radiation workers. The objective of the ionising radiation studies in RAD is to address outstanding questions in ionising radiation research and protection, namely the effects of exposure pattern, of radiation type and of factors that may modify radiationinduced risks (including host and environmental factors). Recent years have seen an unprecedented increase in the number and diversity of sources of non-ionising electromagnetic fields (EMF), principally

Special Training Award Mr Laurent Voisin (until 22 February 2006)

extremely low frequency (ELF) and radio frequency (RF) fields used for individual, industrial and commercial purposes. Although these technologies have made our lives easier, they have brought with them concerns about possible health risks associated with their use. At IARC, work on EMF has mainly focused on RF exposure, which can occur in a number of ways in occupational and environmental settings. In 2006–2007, work in RAD has focused on the evaluation of the cancer consequences of Chernobyl on the occasion of the 20th anniversary of the accident, on the analysis of studies of the effects of low doses of ionising and nonionising radiation and on establishing and conducting new studies of gene-radiation interactions and of the effects of U and Pu isotopes. Ionising radiation Work on the consequences of the Chernobyl accident included the conduct and publication of reviews of the epidemiological evidence concerning cancer risk following the accident (in the framework of the UN Chernobyl Forum – Cardis, Howe et al, 2006; Kesminiene and Cardis, 2007), the evaluation of the likely cancer burden from the accident in Europe as a whole (IARC Working Group on Cancer Following the Chernobyl accident – Cardis, Krewski et al, 2006) and the publication of results of an ecological study

24

Radiation Group

of breast cancer risk in the most contaminated districts (Pukkala et al, 2006). With the exception of thyroid cancer in the most contaminated regions, studies to date do not indicate any increase in cancer risk that can be clearly attributed to radiation from the Chernobyl accident. Studies are few, however, and methodologically limited. Further, because of the long induction period for most cancers, it is too early to evaluate the full radiological impact of the accident. Risk projections suggest that Chernobyl may have caused about 1000 cases of thyroid cancer and 4000 cases of other cancers in Europe by now (about 0.01% of all cancers in the period since the accident). By 2065, models predict that about 16 000 (95%UI 3400–72 000) cases of thyroid cancer and 25 000 (95%UI 11 000–59 000) cases of other cancers may be expected due to radiation (compared to several hundred million cancer cases due to other causes). Although these estimates are subject to considerable uncertainty, they provide an indication of the order of magnitude of the possible impact of the accident. Results of the ecological study of breast cancer incidence in Belarus and Ukraine suggests a radiation-related increase in the most contaminated districts (Pukkala et al, 2006). This increase, which is strongest in those exposed at young ages, needs confirmation in well-designed analytical epidemiological studies with careful reconstruction of individual organ doses. Case-control studies of leukaemia, non-Hodgkin lymphoma (NHL) and thyroid cancer among Chernobyl liquidators from Belarus, Estonia, Latvia, Lithuania and Russia have been conducted to evaluate the effects of low-dose protracted exposures to ionising radiation. The studies include 117 cases of leukaemia and NHL, 127 cases of thyroid cancer and 1272 matched controls. Most subjects received very low doses (median 13 mGy). For all hematological malignancies combined, a significantly elevated OR was seen at doses of 200mGy and above. Risk estimates for leukaemia are slightly higher than, but statistically compatible with, those obtained in atomic bomb survivors and recent low dose-rate studies (Kesminiene et al, submitted).

Analyses of data from the International Collaborative Study of Cancer Risk among Radiation Workers, a retrospective cohort study of cancer mortality among nuclear industry workers in 15 countries conducted in order to provide precise direct estimates of risk after protracted low-dose exposures, have continued, mainly focusing on risk of specific cancer types and of non-cancer outcomes. Analyses included 407 391 workers individually monitored for external radiation with a total follow-up of 5.2 million person-years. The risk for all cancers was significantly associated with radiation dose. Among 31 specific types of malignancies studied, a significant association was found between cumulative external radiation dose and the risk of lung cancer; borderline significant associations were also seen for multiple myeloma and ill-defined and secondary cancers. Despite the size of the study, it was difficult to evaluate the role of radiation on many specific types of cancer because the numbers of deaths were small (Cardis, Vrijheid et al, 2007). There was little evidence for a relationship between mortality from non-malignant diseases and radiation dose (Vrijheid, Cardis et al, 2007). In that study, the estimation of risk associated with radiation exposure is most difficult for lung cancer, because of the potential confounding effect of smoking and of internal radionuclide contamination. A case-control study of lung cancer and of leukaemia among U and Pu workers in the nuclear industry was established, nested within relevant cohorts in Europe (Belgium, France and the United Kingdom). Data collection is underway and is expected to be complete by mid-2008. The study will include approximately 600 lung cancers, 70 leukaemias and their controls. Analyses of the role of 131I on the risk of thyroid cancer have been conducted, through the conduct of combined analyses of the data from several studies (Chernobyl, Marshall Islands, French Polynesia, Hanford USA) of young people exposed to this radionuclide. Results, which will be shortly submitted for publication, confirm the findings of the IARC based case–control study in Belarus and Russia and suggest that even relatively

low doses of 131I have the potential to increase the risk of thyroid cancer following exposure in childhood. A number of recent studies suggest that carriers of pathogenic alleles in DNA repair and damage recognition genes may have an increased risk of breast cancer following exposure to ionising radiation, even at low doses (Cardis, Hall and Tavitigian, 2007). The GENE-RADRISK project was set-up in 2006 to formally evaluate this. It focuses on the conduct of multinational studies (France, Italy, the Netherlands and the United Kingdom) of pre-menopausal breast cancer risk in populations chosen on the basis of high prevalence of radiation exposure (cancer survivors) and/or high prevalence of known mutations in susceptibility genes (BRCA1 and BRCA2 mutation carriers). To date, 523 cases of breast cancer have been identified in the cancer survivor cohorts and 1342 cases in the mutation carrier cohorts. Data and biological sample collection are underway and are expected to be completed by fall 2008. The issue of cancer risk from paediatric CT exposure and other high-dose diagnostic procedures (including interventional radiology) is one of great concern currently in the general public, as well as in the health and radiation protection communities. A group of investigators interested in studying this relationship has been assembled, and information is currently being collected to evaluate the feasibility of a multinational study of this issue. Non-ionising radiation The INTERPHONE Study, a series of multinational case–control studies conducted to determine whether mobile telephone use increases the risk of cancer and, specifically, whether the radiofrequency radiation emitted by mobile telephones is carcinogenic, is nearing completion. Separate studies have been carried out for acoustic neurinoma, glioma, meningioma and tumours of the parotid gland. The studies used a common core protocol and were carried out in Australia, Canada, Denmark, Finland, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Sweden and the United Kingdom. Details of the study protocol 25

Biostatistics and Epidemiology Cluster

Table 1 – Summary of published results from national INTERPHONE analyses of mobile phone use Country

Age range

Diagnosis years

Denmark (Christensen et al, 2005)

20-69

2000-2002

France (Hours et al, 2007)

30-59

Germany (Schuz et al, 2006)

30-69

2000-2003

Norway 19-69 (Klaeboe et al, 2007)

2001-2002

Sweden (Lonn et al, 2005)

20-69

UK (Hepworth et al, 18-69 2006)

Number of cases and controls

OR and 95% CI Ever regular use # cases

Low-grade 81 155 High-grade 171 330

Low-grade 1.08 (0.58,2.00) High-grade 0.58 (0.37,0.90)

96

OR and 95% CI Start of use 10 years or more in the past # cases

OR and 95% CI Ipsilateral use, start of use 10+ years in past # cases

OR and 95% CI Contralateral use, start of use 10 + years in past # cases

Glioma

Nordic combined (Lahkola et al, 2007)

Low-grade 47 1.64 (0.44, 6.12) High-grade 59 0.48 (0.19, 1.26)

6 8 NA

NA

46 months+ 1.15 (0.65,2005) 59 1.96 (0.74,5.20)

21 NA

NA

366 1,494

0.98 (0.74,1.29) 138

2.20 (0.94,5.11)

12 NA

NA

289 358

0.6 (0.4,0.9)

161

6+ years C 0.8 (0.5,1.2)

6+ years 70 1.3 (0.8,2.1)

39

6+ years 0.8 (0.5,1.4)

32

2000-2002

371 674

0.8 (0.6,1.0)

214

0.9 (0.5, 1.5)

25 1.6 (0.8,3.4)

15

1.3 (0.5,3.9)

5

2000-2004

966 1,1716

0.94 (0.78,1.13) 508 0.90 (0.63,1.28)

2000-2004

1,522 3,301

0.78 (0.68,0.91) 867 0.95 (0.74, 1.23) 143 1.39 (1.01,1.92) 77

0.98 (0.71,1.37) 67

2001-2003 96

66 NA

NA

Meningioma Denmark (Christensen et al, 2005)

20-69

2000-2002

175

316

0.83 (0.54,1.28) 67

1.02 (0.32,3.24)

NA

NA

France (Hours et al, 2007)

30-59

2001-2003

145 145

0.74 (0.43-1.28) 71

46 months+ NA 0.73 (0.28,1.91) 15

NA

Germany (Schuz et al, 2006)

30-69

2000-2003

381 762

0.84 (0.62,1.13) 104 1.09 (0.35,3.37)

Norway (Klaeboe et al 2007)

19-69

2001-2002

207 358

26

0.8 (0.5,1.1)

98

6+ years 1.0 (0.6,1.8)

6

5

36

NA

6+ years 1.1 (0.6,2.3)

NA

17

6+ years 1.2 (0.6,2.3) 18

Radiation Group

Table 1 (contd) Country

Age range

Diagnosis years

Number of cases and controls

OR and 95% CI Ever regular use # cases

Sweden (Lonn et al, 2005)

20-69

2000-2002

273 674

0.7 (0.5,0.9)

0.90 (0.51,1.57) 45

OR and 95% CI Start of use 10 years or more in the past # cases

OR and 95% CI Ipsilateral use, start of use 10+ years in past # cases

OR and 95% CI Contralateral use, start of use 10 + years in past # cases

1.3 (0.5,3.9) 5

0.5 (0.1, 1.7)

0.22 (0.04,1.11) 2

NA

NA

0.92 (0.53,1.59) 58

46 months+ 0.66 (0.28,1.57) 14

NA

NA

118

0.9 (0.4, 1.9)

8

3

Acoustic neurinoma Denmark (Christensen et al, 2004)

20-69

2000-2002

106 212

France (Hours et al, 2007)

30-59

2001-2003

109

Germany (Schlehofer et al, 2007)

30-69

2000-2003

Japan (Takebayashi et al, 2006)

30-69

2000-2004

Norway (Klaeboe et al 2007)

19-69

Sweden (Lonn et al, 2004)

20-69

Nordic combined (Schoemaker et al, 2005)

214

97

194

0.67 (0.38,1.19) 29

NA

0

NA

NA

101

339

0.73 (0.43, 1.23) 51

8+ years 0.79 (0.24,2.65)

4

NA

NA

45

358

0.5 (0.2,1.0)

22

6+ years 0.5 (0.2, 1.4)

8

6+ years 0.9 (0.3, 2.8) 5

6+ years 0.8 (0.2,2.5)

1999-2002

148

604

1.0 (0.6, 1.5)

89

1.9 (0.9, 4.1)

14

3.9 (1.6, 9.5) 12

0.8 (0.2, 2.9) 4

1999-2004

678 3,553

0.9 (0.7, 1.1)

360

1.0 (0.7, 1.5)

47

1.3 (0.8, 2.0) 31 1.8 (1.1-3.1)* 23

1.0 (0.6,1.7) 20 0.9 (0.5, 1.8)* 12

Benign 2.6 (0.9, 7.9) Malignant 0.7 (0.1, 5.7)

Benign 0.3 (0.0, 2.3) Malignant NA

2001-2002

4

Parotid gland tumours Sweden and Denmark (Lonn et al, 2006)

20-69

2000-2002

Benign 112 321 Malignant 60 681

Benign 00.9 (0.5,1.5) Malignant 0.7 (0.4, 1.3)

77 25

Benign 1.4 (0.5, 3.9) Malignant 0.4 (0.1, 2.6)

7 2

6 1

1 0

* Analysis by duration of use instead of time since start of use.

27

Biostatistics and Epidemiology Cluster

and procedures have been published (Cardis, Richardson et al, 2007). The study includes approximately 2600 gliomas, 2300 meningiomas, 1100 acoustic neurinomas, 400 parotid gland tumours and their respective controls. This is by far the largest epidemiological study of these tumours to date. A number of methodological papers have been submitted or published (Vrijheid, Deltour et al, 2006; Vrijheid, Cardis et al, 2006; Cardis, Richardson et al, 2007; Berg et al, 2005; Hepworth et al, 2006; Parslow et al, 2003; Sadetzki et al, 2007; SamkangeZeeb et al, 2004; Lakhola et al, 2005), addressing issues of study design, participation bias, recall error and exposure assessment that are essential in the interpretation of results from the study. Results of national analyses of the relation between mobile phone use and risk of specific tumour types in some of the participating countries have been published (Christensen et al 2004, 2005; Hepworth et al, 2006; Hours et al, 2007; Klaeboe et al, 2007; Lahkola et al, 2007; Lonn et al, 2004, 2005, 2006; Schlehofer et al, 2007; Schoemaker et al, 2006; Schuz et al, 2006; Takebayashi et al, 2006) and are summarised in Table 1. In most studies, the OR related to ever having been a regular mobile phone user was below 1.0, in some instances statistically significantly so, possibly reflecting participation bias or other methodological limitations. For glioma, although results by time since start of use and amount of phone use vary, the number of long-term users is small in individual countries, and results are therefore compatible. Pooling of data from Nordic countries and part of the United Kingdom yielded a significantly increased risk of glioma related to use of mobile phones for a period of 10 years or more on the side of the head where the tumour developed (Lahkola et al, 2007). This finding could either be causal or artifactual, related to differential recall between cases and controls. For meningioma and acoustic neurinoma, most national studies provided little evidence of an increased risk. The numbers of long-term and heavy users in individual studies were even smaller than for glioma, however, and prevent any definitive conclusion about a possible 28

association between mobile telephone use and the risk of these tumours. A pooled analysis of data from Nordic countries and the United Kingdom found a significantly increased risk of acoustic neurinoma related to durations of use of 10 years or more on the side of tumour (Schoemaker et al, 2006). Little can be said at present concerning the risk of parotid gland tumours related to mobile telephone use. Manuscripts presenting results of the international analyses, based on much larger numbers of long-term and heavy users, are in preparation. More detailed analyses are also underway, focusing on more precise localisation of tumors using 3-dimensional radiological images, and on the analysis of the effect of RF exposure at the location of the tumor, using a gradient of RF emitted by mobile phones. Adjustment for exposure measurement error based on data from the validation studies is also being conducted in order to assess the impact of these errors on risk. Results of national analyses of the relation between other risk factors and the tumours of interest have also been published (Berg et al, 2996; Blettner et al, 2006; Edwards et al, 2006; Malmer et al, 2007; Schlehofer et al, 2007; Schoemaker et al, 2006, 2007a, 2007b; Schuz et al, 2006; Schwartzbaum et al, 2005, 2007; Wigertz et al, 2006, 2007). These include smoking, allergies, environmental and occupational risk factors, medical radiation and genes. Work is beginning to further exploit the information on occupational exposures collected within the INTERPHONE study with the aims of: 1) evaluating the possible association between occupational exposure to EMF (both ELF and RF/MW) and glioma and meningioma; 2) evaluating the possible association between selected occupational chemical exposures and these tumours and 3) investigating the possibility of synergism and/or confounding between chemical and EMF exposures on the risk of brain cancers. This work involves assessing occupational exposure to EMF and selected chemicals using validated job-exposure matrices, which will be developed within the project and refining this assessment by consolidating information obtained from

the JEM with data on exposure variations related to the specific industry in which a subject worked, to the tasks he or she performed and to the actual sources of exposure, available from the INTERPHONE questionnaire. The Radiation Group continues its involvement in a number of multinational projects aimed at pooling resources of international and national agencies and key scientific institutions working on the biological effects of electromagnetic fields in order to assess health effects of exposure to static and time-varying EMFs. These include: • The WHO International EMF Project, in which the Radiation Group at IARC provides assistance in the evaluation of health risks from EMF, the identification of gaps in scientific knowledge and recommendations about research protocols. • The EU-funded EMF-Net consortium aimed at collating and critically evaluating results of research activities on the biological effects of EMF, with the aim of providing policy relevant interpretation and advice for the facilitation of policy development in non-ionising radiation protection. Within this consortium, the head of the Radiation Group is part of the Steering Committee and the Fast Response Team, and is responsible for a work package on the epidemiology of EMF. Methodological developments Errors in the estimation of exposures or doses are well recognised to be a major source of uncertainty in epidemiological studies of cancer and other chronic diseases, particularly for ionising and non-

Radiation Group

ionising radiation. A method to take these errors into account in the risk estimates has been developed and implemented, using Monte Carlo simulations (Stayner et al, in press). Dose reconstruction Extensive efforts have been made to develop, test and implement dosimetric models for reconstruction of radiation doses following the Chernobyl accident

(Drozdovitch, Maceika et al, 2007; Drozdovitch, Bouville et al, 2007) and atmospheric weapons tests in French Polynesia (Drozdovitch et al, submitted) and to characterise and quantify errors in occupational radiation doses in studies of nuclear industry workers (Thierry-Chef et al, 2007) for use in the epidemiological studies conducted by the group. A method (RADRUE - Realistic Analytical Dose

Reconstruction with Uncertainty Estimation) was developed for calculating external doses to liquidators (Kryuchkov et al, submitted). Work is also underway to estimate RF energy absorbed in different anatomical locations of the brain for the INTERPHONE study. All dose reconstruction efforts include an assessment of sources of uncertainty.

The RAD Group is grateful to the following for their collaboration in its projects: Alexandre Abrosimov, Obninsk, Russian Federation; Yoon-Ok Ahn, Seoul, Korea; Suminori Akiba, Kagoshima, Japan; Yadviga Anoshko, Minsk, Belarus; Lynn Anspaugh, Utah, USA; Larisa Astakhova, Minsk, Belarus; Bruce Armstrong, Camperdown, Australia; Patrick Ashmore, Ottawa, Canada; Will Atkinson, Oxfordshire, United Kingdom; Anssi Auvinen, Tampere, Finland; Jong-Myon Bae, Seoul, Korea; Elena Bakhanova, Kiev, Ukraine; Jacques Bénichou, Rouen, France; Philippe Bérard, Gif-sur-Yvette, France; Gabriele Berg, Bielefeld, Germany; Francis Bermann, Paris, France; Juan Bernar, Madrid, Spain; Marie-Odile Bernier, Fontenay-aux-Roses, France; Alain Biau, Fontenay-aux-Roses, France; Derek Bingham, Aldermaston, United Kingdom; Keith Binks, Cumbria, United Kingdom; Alan Birchall, Oxon, United Kingdom; Eric Blanchardon, Fontenay-aux-Roses, France; Maria Blettner, Mainz, Germany; André Bouville, Bethesda, USA; Joseph Bowman, Cincinnati, USA; Julianne Brown, Sydney, Australia; Richard Bull, Didcot, United Kingdom; Jochen Buschmann, Hannover, Germany; Matthew Carroll, Sydney, Australia; Cécile Challeton-de Vathaire, Fontenay-aux-Roses, France; Lawrence Challis, Didcot, UK; Sergey Chekin, Obninsk, Russian Federation; Gabriel Chodick, Bethesda, USA; Helle Collatz Christensen, Copenhagen, Denmark; Vadim Chumak, Kiev, Ukraine; David Conover, Cincinnati, USA; Angus Cook, Western Australia; Georges Cowper, Ontario, Canada; Nigel Cridland, Didcot, UK; Pascal Deboodt, Mol, Belgium; Sarah Darby, Oxford, UK; Carlos del Pozo, Ispra, Italy; Florent de Vathaire, Fontenay-aux-Roses, France; Evgenyi Demidchik, Minsk, Belarus; Asuncion Diez Sacristan, Madrid, Spain; Gugliemo d’Inzeo, Rome, Italy; Monika Eklöf, Osthammar, Sweden; Douglas Easton, Cambridge, United Kingdom; Hilde Engels, Mol, Belgium; Göran Engholm, Uppsala, Sweden; Maria Feychting, Stockholm, Sweden; Jack Fix, Richland, USA; Gerd Freidrich, Bonn, Germany; Rosaria Galanti, Stockholm, Sweden; Sara Gandini, Milan, Italy; Vladimir Gapanovich, Minsk, Belarus; Yuryi Gavrilin, Moscow, Russian Federation Ethel Gilbert, Rockville, Maryland, USA; David Goldgar, Utah, USA; Ivan Golovanov, Moscow, Russian Federation; Genadyi Goulko, Würzburg, Germany; Birute Griciene, Vilnius, Lithuania; Liudmila Gulak, Kiev, Ukraine; Gabriel Gulis, Esbjerg, Denmark; Rima Habib, Beirut, Lebanon; Celia Hacker, Menai, Australia; Matti Hakama, Tampere, Finland Janet Hall, Orsay, France; Per Hall, Stockholm, Sweden; Gael Hammer, Mainz, Germany Kjell Hansson Mild, Umea, Sweden; Riccardo Haupt, Genova, Italy; Mike Hawkins, Birmingham, United Kingdom; Bruce Heinmiller, Ontario, Canada; Michel Henry-Amar, Caen, France; Catherine Hill, Villejuif, France; Karol Holan, Bratislava, Slovak Republic; Masaharu Hoshi, Hiroshima, Japan ; Martine Hours, Lyon, France; Geoffrey Howe, New York, USA; Philippe Hubert, Paris, France; Christian Hurtgen, Mol, Belgium; Hannu Hyvonen, Helsinki, Finland; Ivano Iavarone, Rome, Italy; Sergey Illichev, Chernobyl, Ukraine; Masahiro Ito, Nagasaki, Japan; Viktor Ivanov, Obninsk, Russian Federation; Christoffer Johansen, Copenhagen, Denmark; Jukka Juutilainen, Kuopio, Finland; Magnus Kaijser, Stockholm, Sweden; John Kaldor, Darlinghurst, Australia; Eleonora Kapitonova, Gomel, Belarus; Jolanta Karpowicz, Warsaw, Poland; Andor Kerekes, Budapest, Hungary ; Svetlana Khayt, Obninsk, Russian Federation; Valery Khrouch, Moscow, Russian Federation; Vicki Kirsh, Toronto, Canada; Victor Krjutchkov, Moscow, Russian Federation; Lars Klaeboe, Oslo, Norway; Elena Korobova, Moscow, Russian Federation ; Lina Kovgan, Kiev, Ukraine; Daniel Krewski, Ottawa, Canada; Juozas Kurtinaitis, Vilnius, Lithuania; Pentti Kyyronen, Finland; Susanna Lagorio, Rome, Italy; Bryan Langholz, Los Angeles, USA; Froydis Langmark, Oslo, Norway; Dominique Laurier, Fontenay-aux-Roses, France; Myung-Chul Lee, Seoul, Korea; Norbert Leitgeb, Graz, Austria; Ilya Likhtarev, Kiev, Ukraine ; Martha Linet, Rockville, USA; Mark Little, London, United Kingdom; Stefan Lonn, Stockholm, Sweden; Nickolas Luckyanov, Bethesda, USA; Eugeny Lushnikov, Obninsk, Russian Federation; Corrado Magnani, Turin, Italy ; Patricia McKinney, Leeds, United Kingdom; Marat Maksioutov, Obninsk, Russian Federation; Irina Malakhova, Minsk, Belarus; Hans Malker, Sweden; Simon Mann, Didcot, United Kingdom; Mike Marshall, Didcot, United Kingdom; Marco Martuzzi, Switzerland; Albinas Mastauskas, Vilnius, Lithuania; Vladimir Masyakin, Gomel, Belarus; Mary

29

Biostatistics and Epidemiology Cluster

McBride, Vancouver, Canada; Alistair McKinlay, Didcot, UK; Anatolyi Mirkhaidarov, Gomel, BelarusTorgil Möller, Lund, Sweden; Mirjana Moser, Bern, Switzerland; Colin Muirhead, Oxon, United Kingdom ; William Murray, Cincinnati, USA; Louise Nadon, Laval des Rapides, Canada; Eva Negri, Milan, Italy; Catherine Noguès, Saint-Cloud, France; Jorgen H. Olsen, Copenhagen, Denmark; Demosthenes Papamelethiou, Ispra, Italy; Marie-Elise Parent, Laval des Rapides, Canada; Vladimir Parshin, Obninsk, Russian Federation; Eugenyi Parshkov, Obninsk, Russian Federation; Mark Pearce, New Castle, United Kingdom; Frantisek Pernika, Vienna, Austria; Aldo Pinchera, Pisa, Italy ; Semyon Poliakov, Minsk, Belarus; Eero Pukkala, Helsinki, Finland; Matthew Puncher, Oxon, United Kingdom; Paolo Ravazzani, Milan, Italy; David Richardson, Chapel Hill, USA; Tony Riddell, Cumbria, United Kingdom; Rodriguez-Artalejo, Madrid, Spain; Agnès Rogel, Fontenay-aux-Roses, France; Cecile Ronckers, Amsterdam, The Netherlands; Siegal Sadetzki, Tel Aviv, Israel; Tiina Salminen, Tampere, Finland ; Theodoros Samaras, Thessaloniki, Greece; Risto Sankila, Helsinki, Finland; Elena Sasnovskaya, Gomel, Belarus; Mikhail Savkin, Moscow, Russian Federation; Yoshisada Shibata, Nagasaki, Japan; Brigitte Schlehofer, Heidelberg, Germany; Minouk Schoemaker, Sutton, United Kingdom; Mary Schubauer-Berigan, Cincinnati, USA; Joachim Schuez, Copenhagen, Denmark; Natalya Shchukina, Obninsk, Russian Federation; Jack Siemiatycki, Montréal, Canada; Steve Simon, Rockville, USA; Aivars Stengrevics, Riga, Latvia; Hans Storm, Copenhagen, Denmark; Anthony Swerdlow, Sutton, United Kingdom; Toru Takebayashi, Tokyo, Japan; Masao Taki, Tokyo, Japan; Mare Tekkel, Tallinn, Estonia; Maylis Telle-Lamberton, Fontenay-auxRoses, France ; Duncan Thomas, Los Angeles, USA; Geraldine Thomas, Swansea, United Kingdom; Gyorgy Thuroczy, Budapest, Hungary; Margot Tirmarche, Fontenay-aux-Roses, France; Klaus Trott, Northwood, United Kingdom; Philipp Trueb, Bern, Switzerland; Anatoly Tsyb, Obninsk, Russian Federation; Aleksan Tsykalo, Kiev, Ukraine; Aleksan Tukov, Moscow, Russian Federation; Istvan Turai, Geneva, Switzerland; Tore Tynes, Oslo, Norway; Massimo Usel, Geneva, Switzerland ; David Utterback, Cincinnati, USA; Flora Van Leeuwen, Amsterdam, The Netherlands; Martie van Tongeren, Manchester, United Kingdom; Paolo Vecchia, Rome, Italy; Katalin Veress, Budapest, Hungary; Bernard Veyret, Bordeaux, France; Jean-François Viel, Besançon, France; Oleg Vlasov, Obninsk, Russian Federation; Joe Wiart, Issy-les-Moulineaux, France; Richard Wilkins, Berkshire, United Kingdom; Dillwyn Williams, Cambridge, United Kingdom; Alistair Woodward, Auckland, New Zealand; Naohito Yamaguchi, Tokyo, Japan; Shunichi Yamashita, Nagasaki, Japan; Takesumi Yoshimura, Fukuoka, Japan. Financial Support from the following bodies is gratefully acknowledged: European Commission US National Cancer Institute Fondation Santé et Radiofréquences, France Bundesamt für Strahlenschutz, Germany Office Fédéral de la Santé publique, Switzerland World Health Organization Publications Ahlbom A, Feychting M, Cardis E, Elliott P (2007). Re: Schüz et al. Cellular Telephone Use and Cancer Risk: Update of a Nationwide Danish Cohort Study. JNCI; 99, 655-655. Letter to the editor. Andrieu N, Easton D, Chang-Claude J, Rookus MA, Brohet R, Cardis E, Antoniou AC, Peock S, EMBRACE, Noguès C, GENEPSO, Van Leeuwen FE, GEO-HEBON, the IBCCS collaborators group and Goldgar DE (2006). Low-dose ionizing radiation significantly increases the risk of breast cancer among BRCA1/2 mutation carriers in the IBCCS Study. J Clin Oncol; 24(21):3361-6. Armstrong BG, Dolk H, Pattenden S, Vrijheid M, Loane M, Rankin J, Dunn C, Grundy C, Abramsky L, Boyd PA, Stone D, Wellesley D.

30

Geographic variation and localised clustering of congenital anomalies in Britain. Emerg Themes Epidemiol. 2007 Jul 6;4:14-20. Bouville A, Likhtarev I, Kovgan L, Minenko V, Shinkarev S, Drozdovitch V. Radiation dosimetry for highly contaminated Ukrainian, Belarusian and Russian populations, and for less contaminated populations in Europe. Health Phys (submitted). Cardis E. Commentary: low dose-rate exposures to ionizing radiation. Int J Epidemiology 2007; doi: 10.1093/ije/dym192. Cardis E. Ongoing and Future Research Needs for Achieving a Better Understanding of the Consequences of Nuclear Emergencies. Health Physics (in press). Cardis E, Hall J, Tavtigian SV. Identification of women with an increased risk of developing

radiation-induced breast cancer. Breast Cancer Res. 2007;9(3):106. Cardis E, Richardson L, Deltour I, Armstrong B, Feychting M, Johansen C, Kilkenny M, McKinney P, Modan B, Sadetzki S, Schuz J, Swerdlow A, Vrijheid M, Auvinen A, Berg G, Blettner M, Bowman J, Brown J, Chetrit A, Christensen HC, Cook A, Hepworth S, Giles G, Hours M, Iavarone I, Jarus-Hakak A, Klaeboe L, Krewski D, Lagorio S, Lonn S, Mann S, McBride M, Muir K, Nadon L, Parent ME, Pearce N, Salminen T, Schoemaker M, Schlehofer B, Siemiatycki J, Taki M, Takebayashi T, Tynes T, van Tongeren M, Vecchia P, Wiart J, Woodward A, Yamaguchi N (2007). The INTERPHONE study: design, epidemiological methods, and description of the study population. Eur J Epidemiol 22: 647-664.

Radiation Group Cardis E, Vrijheid M, Blettner M, Gilbert E, Hakama M, Hill C, Howe G, Kaldor J, Muirhead CR, Schubauer-Berigan M, Yoshimura T, Bermann F, Cowper G, Fix J, Hacker C, Heinmiller B, Marshall M, ThierryChef I, Utterback D, Ahn Y-O, Amoros E, Ashmore P, Auvinen A, Bae J-M, Bernar JS, Biau A, Combalot E, Deboodt P, Diez Sacristan A, Eklof M, Engels H, Engholm G, Gulis G, Habib R, Holan K, Hyvonen H, Kerekes A, Kurtinaitis J, Malker H, Martuzzi M, Mastauskas A, Monnet A, Moser M, Pearce MS, Richardson DB, Rodriguez-Artalejo F, Rogel A, Tardy H, Telle-Lamberton M, Turai I, Usel M, Veress K. (2007). The 15-Country Collaborative Study of Cancer Risk Among Radiation Workers in the Nuclear Industry: Estimates of Radiation Related Cancer Risks. Radiation Research; 167, 396-416. Cardis E, Howe G, Ron E, Balonov M, Bebeshko V, Buglova E, Bogdanova T, Bouville A, Carr Z, Chumak V, Davis S, Demidchik Y, Drozdovitch V, Gentner N, Gudzenko N, Hatch M, Ivanov V, Jacob P, Kapitonova E, Kenigsberg J, Kesminiene A, Kopecky K, Kryuchkov V, Likhtarev I, Loos A, Pinchera A, Reiners C, Repacholi M. Shibata Y, Shore R, Thomas G, Tirmarche M, Wachholz B, Yamashita S, Zvonova I (2006). Cancer Consequences Of The Chernobyl Accident: 20 Years After. Journal of Radiological Protection; 26(2):127-40. Cardis E, Krewski D, Boniol M, Drozdovitch V, Darby SC, Gilbert ES, Akiba S, Benichou J, Ferlay J, Gandini S, Hill C, Howe G, Kesminiene A, Moser M, Sanchez M, Storm H, Voisin L, Boyle P (2006). Estimates of the Cancer Burden in Europe from Radioactive Fallout from the Chernobyl Accident. Int J Cancer; 119(6):1224-35. Cardis E, Kesminiene A (2006). Response to Scott. Risk of Thyroid Cancer After Exposure to 131I in Childhood. JNCI; 98(8);561. Drozdovitch V, Bouville A, Chobanova N, Filistovitch V, Ilus T, Kovačić M, Malátová I, Moser M, Nedveckaite T, Völkle H, Cardis E (2007). Radiation exposure to the population of Europe following the Chernobyl accident. Radiat Prot Dosimetry. 123(4):515-28. Drozdovitch V, Germenchuk M, Bouville A (2006). Using total beta-activity measurements in milk to derive thyroid doses from Chernobyl fallout. Radiat Prot Dosimetry. 2006; 118(4):402-11. Drozdovitch V, Khrouch V, Bouville A, Goulko G, Zvonova I, Cardis E (2006). Risk of thyroid cancer after exposure to I131 in childhood –

Response to Grossman and Nussbaum. Journal of the National Cancer Institute. 98(9); 641. Drozdovitch V, Maceika E, Khrouch V, Zvonova I, Vlasov O, Bouville A, Cardis E. Uncertainties in individual doses in a case control study of thyroid cancer after the Chernobyl accident. Radiat Prot Dosimetry. 2007 Jul 18; [Epub ahead of print]. Gilbert ES, Thierry-Chef I, Cardis E, Fix JJ, Marshall M (2006). External dose estimation for nuclear workers studies. Radiation Research;166:168-73. Hours M, Bernard M, Montestrucq L, Arslan M, Bergeret A, Deltour I, Cardis E. [Cell Phones and Risk of brain and acoustic nerve tumours: the French INTERPHONE casecontrol study.] Rev Epidemiol Sante Publique. 2007 Sep 10; [Epub ahead of print] French. Hours M, Montestrucq L, Arslan M, Bernard M, El Hadjimoussa H, Vrijheid M, Deltour I, Cardis E (2007). Validation des outils utilisés pour la mesure de la consommation téléphonique mobile dans l’étude INTERPHONE en France. Environnement, risques et Santé. Volume 6 (2), 101-9. Kesminiene A, Cardis E (2007). Epidémiologie de l’après-Tchernobyl. Bulletin du Cancer. Volume 94 (5) 423-30. Minenko VF, Ulanovsky AV, Drozdovitch VV, Shemiakina EV, Gavrilin YI, Khrouch VT, Shinkarev SM, Voilleque PG, Bouville A, Anspaugh LR, Luckyanov N (2006). Individual thyroid dose estimates for a case-control study of Chernobyl-related thyroid cancer among children of Belarus--part II. Contributions from long-lived radionuclides and external radiation. Health Phys; 90(4):312-27. National Research Council (2006). Health Risks From Exposure to Low Levels of Ionizing Radiation: BEIR VII Phase 2 Committee to Assess Health Risks from Exposure to Low Levels of Ionizing Radiation, National Research Council http://books.nap.edu/catalog/11340.html. Pukkala E, Kesminiene A, Poliakov S, Ryzhov A, Drozdovich V, Kovgan L, Kyyrönen P, Malakhova I, Gulak L, Cardis E (2006). Breast cancer in Belarus and Ukraine after the Chernobyl accident. Int J Cancer;119(3):651-8. Sadetzki S, Chetrit A, Jarus-Hakak A, Cardis E, Deutch Y, Duvdevani S, Zultan A, Novikov I, Freedman L, Wolf M. Cellphone use and risk of benign and malignant parotid gland tumors - a nationwide case-control study. Am J Epid (in press).

Schoemaker MJ, Swerdlow AJ, Ahlbom A, Auvinen A, Blaasaas KG, Cardis E, Christensen HC, Feychting M, Hepworth SJ, Johansen C, Klaeboe L, Lonn S, McKinney PA, Muir K, Raitanen J, Salminen T, Thomsen J, Tynes T (2005). Mobile phone use and risk of acoustic neuroma: results of the Interphone case-control study in five North European countries. Br J Cancer; 93(7):842-8. Stayner L, Vrijheid M, Cardis E, Stram DO, Deltour I, Gilbert SJ, Howe G. Monte Carlo maximum likelihood methods for estimating uncertainty arising from shared errors in exposures in epidemiological studies. Radiation Research (in press). Straume T, Anspaugh LR, Marchetti AA, Voigt G, Minenko V, Gu F, Men P, Trofimik S, Tretyakevich S, Drozdovitch V, Shagalova E, Zhukova O, Germenchuk M, Berlovich S (2006). Measurement of 129 I and 137 Cs in soils from Belarus and reconstruction of 131I deposition from the Chernobyl accident. Health Phys.; 91(1):7-19. Thierry-Chef I, Marshall M, Fix JJ, Bermann F, Gilbert ES, Hacker C, Heinmiller B, Murray W, Pearce MS, Utterback D, Bernar J, Deboodt P, Eklof M, Griciene B, Holan K, Hyvonen H, Kerekes A, Lee M-C, Moser M, Pernicka F, E Cardis (2007). The 15-Country Collaborative Study of Cancer Risk Among Radiation Workers in the Nuclear Industry: Study of Errors in Dosimetry. Radiation Research. 167, 380-395. Thierry-Chef I, Simon SL, Miller DL (2006). Radiation dose and cancer risk among pediatric patients undergoing interventional neuroradiology procedures. Pediatr Radiol.;36 Suppl 14:159-62. Vrijheid M, Cardis E, Blettner M, Gilbert E, Hakama M, Hill C, Howe G, Kaldor J, Muirhead CR, Schubauer-Berigan M, Yoshimura T, Ahn Y-O, Ashmore P, Auvinen A, Bae J-M, Engels H, Gulis G, Habib R, Hosoda Y, Kurtinaitis J, Moser M, RodriguezArtalejo F, Rogel A, Telle-Lamberton M, Turai I, Usel M, Veress K (2007). The 15-Country Collaborative Study of Cancer Risk Among Radiation Workers in the Nuclear Industry: Design, Epidemiological Methods, and Descriptive Results. Radiation Research. 167, 361-379. Vrijheid M, Deltour I, Krewski D, Sanchez M, Cardis E (2006). The effects of recall errors and of selection bias in epidemiologic studies of mobile phone use and cancer risk. J Expo Sci Environ Epidemiol. Jul;16(4):371-84.

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Biostatistics and Epidemiology Cluster Vrijheid M, Cardis E, Armstrong BK, Auvinen A, Berg G, Blaasaas KG, Brown J, Carroll M, Chetrit A, Christensen HC, Deltour I, Feychting M, Giles GG, Hepworth SJ, Hours M, Iavarone I, Johansen C, Klæboe L, Kurttio P, Lagorio S, Lönn S, McKinney PA, Montestrucq M, Parslow RC, Richardson L, Sadetzki S, Salminen T, Schüz J, Tynes T, Woodward A (2006). Validation of short-term recall of mobile phone use for the Interphone Study. Occupational and Environmental Medicine; 63(4) :237-43. Vrijheid M, Cardis E, Ashmore P, Auvinen A, Bae JM, Engels H, Gilbert E, Gulis G, Habib R, Howe G, Kurtinaitis J, Malker H, Muirhead C, Richardson D, Rodriguez-Artalejo F, Rogel A, Schubauer-Berigan M, Tardy H, TelleLamberton M, Usel M, Veress K. Mortality from diseases other than cancer following low doses of ionizing radiation: results from the 15Country Study of nuclear industry workers. Int J Epidemiol. 2007 Jul 31; [Epub ahead of print]

Other INTERPHONE references cited: Berg G, Schuz J, Samkange-Zeeb F, Blettner M (2005). Assessment of radiofrequency exposure from cellular telephone daily use in an epidemiological study: German Validation study of the international case-control study of cancers of the brain--INTERPHONE-Study. J Expo Anal Environ Epidemiol;15(3):217-24. Berg G, Spallek J, Schuz J, et al. (2006); Interphone Study Group, Germany. Occupational exposure to radio frequency/microwave radiation and the risk of brain tumors: Interphone Study Group, Germany. Am J Epidemiol;164(6):538-48. Epub 2006 Jul 27. Blettner M, Schlehofer B, Samkange-Zeeb F, et al. (2007). Medical exposure to ionising radiation and the risk of brain tumours: Interphone study group, Germany. Eur J Cancer; 43(13):1990-8. Epub 2007 Aug 8. Christensen HC, Schuz J, Kosteljanetz M, et al. (2005). Cellular telephones and risk for brain tumors: a population-based, incident casecontrol study. Neurology;64(7):1189-95. Erratum in: Neurology. 2005 Oct 25;65(8):1324.

Christensen HC, Schuz J, Kosteljanetz M, et al. (2004). Cellular telephone use and risk of acoustic neuroma. Am J Epidemiol;159(3):277-83. Edwards CG, Schwartzbaum JA, Lonn S, et al. (2006). Exposure to loud noise and risk of acoustic neuroma. Am J Epidemiol;163(4):32733. Epub 2005 Dec 15. Erratum in: Am J Epidemiol. 2006 Jun 15;163(12):1163. Hepworth SJ, Bolton A, Parslow RC, et al. (2006). Assigning exposure to pesticides and solvents from self-reports collected by a computer assisted personal interview and expert assessment of job codes: the UK Adult Brain Tumour Study. Occup Environ Med; 63(4):26772. Hepworth SJ, Schoemaker MJ, Muir KR, et al. (2006). Mobile phone use and risk of glioma in adults: case-control study. Br Med J; 332(7546):883-7. Epub 2006 Jan 20. Klaeboe L, Blaasaas KG, Tynes T (2007). Use of mobile phones in Norway and risk of intracranial tumours. Eur J Cancer Prev;16(2):158-64. Lahkola A, Auvinen A, Raitanen J, et al. (2007). Mobile phone use and risk of glioma in 5 North European countries. Int J Cancer; 120(8):1769-75. Lahkola A, Salminen T, Auvinen A (2005). Selection bias due to differential participation in a case-control study of mobile phone use and brain tumors. Ann Epidemiol; 15(5):321-5.

Schoemaker MJ, Swerdlow AJ, Auvinen A, et al. (2006). Medical history, cigarette smoking and risk of acoustic neuroma: an international case-control study. Int J Cancer; 120(1):10310. Schoemaker MJ, Swerdlow AJ, Hepworth SJ, et al. (2006). History of allergies and risk of glioma in adults. Int J Cancer; 119(9):2165-72. Schoemaker MJ, Swerdlow AJ, Hepworth SJ, et al. (2007) History of allergic disease and risk of meningioma. Am J Epidemiol; 165(5):47785. Epub 2006 Dec 20. Schuz J, Bohler E, Berg G, et al. (2006). Cellular phones, cordless phones, and the risks of glioma and meningioma (Interphone Study Group, Germany). Am J Epidemiol.; 163(6):512-20. Epub 2006 Jan 27. Schuz J, Bohler E, Schlehofer B, et al. (2006). Radiofrequency electromagnetic fields emitted from base stations of DECT cordless phones and the risk of glioma and meningioma (Interphone Study Group, Germany). Radiat Res; 166(1 Pt 1):116-9. Schwartzbaum J, Ahlbom A, Malmer B, et al. (2005). Polymorphisms associated with asthma are inversely related to glioblastoma multiforme. Cancer Res; 65(14):6459-65.

Lonn S, Ahlbom A, Hall P, Feychting M; Swedish Interphone Study Group (2005). Long-term mobile phone use and brain tumor risk. Am J Epidemiol; 161(6):526-35.

Schwartzbaum JA, Ahlbom A, Lonn S, et al. (2007). An international case-control study of glutathione transferase and functionally related polymorphisms and risk of primary adult brain tumors. Cancer Epidemiol Biomarkers Prev; 16(3):559-65.

Malmer BS, Feychting M, Lonn S, et al. (2007). Genetic variation in p53 and ATM haplotypes and risk of glioma and meningioma. J Neurooncol; 82(3):229-37. Epub 2006 Dec 7.

Takebayashi T, Akiba S, Kikuchi Y, et al. (2006). Mobile phone use and acoustic neuroma risk in Japan. Occup Environ Med; 63(12):802-7. Epub 2006 Aug 15.

Parslow RC, Hepworth SJ, McKinney PA (2003). Recall of past use of mobile phone handsets. Radiat Prot Dosimetry; 106(3):23340.

Wigertz A, Lonn S, Mathiesen T, et al; Swedish Interphone Study Group (2006). Risk of brain tumors associated with exposure to exogenous female sex hormones. Am J Epidemiol; 164(7):629-36. Epub 2006 Jul 11.

Samkange-Zeeb F, Berg G, Blettner M (2004). Validation of self-reported cellular phone use. J Expo Anal Environ Epidemiol; 14(3):245-8. Schlehofer B, Schlaefer K, Blettner M, et al. (2007). Environmental risk factors for sporadic

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acoustic neuroma (Interphone Study Group, Germany). Eur J Cancer; 43(11):1741-7. Epub 2007 Jun 27.

Wigertz A, Lonn S, Schwartzbaum J, et al. (2007). Allergic Conditions and Brain Tumor Risk. Am J Epidemiol [Epub ahead of print].

Epidemiology and Biology Cluster (EBC) Cluster Coordinator: Dr Silvia Franceschi The 2006–2007 biennium has been a period of transition for the Epidemiology and Biology Cluster (EBC). For the better part of this period, the EBC included four Groups that carry out studies on avoidable causes of cancer, including infections, nutrition and tobacco. In the spring of 2007, two significant structural changes were put into effect: first, the Tobacco and Cancer (TOB) Group was transformed into the Tobacco and Cancer Team and moved into the newly created Lifestyle, Environment and Cancer (GEE) Group, within the Genetics and Epidemiology Cluster (GEC); second, the staff of the Nutrition and Hormones (NTH) Group joined the newly created Epidemiology Methods and Support Group (BIO) within the Biostatistics and Epidemiology Cluster (BEC) as the Nutritional Database and Resource Team. These changes will allow a better integration of the work on the adverse consequences of smoking and the most effective anti-tobacco strategies into projects on other environmental carcinogens, and the experience acquired in the management of the EPIC studies to serve other cohort studies started or being started at IARC. Thus two Groups—Infections and Cancer Epidemiology (ICE) and Infections and Cancer Biology (ICB) — are presently active in the EBC, a Cluster whose focus is now specifically on the link between infections and cancer. Chronic infections altogether account for nearly 20% of cancer cases worldwide, with lowand intermediate-resource countries hardest hit. Research on the human papillomavirus (HPV ), the cause of cervical cancer and of a sizeable proportion of other cancers of the anogenital tract and oropharynx, is one of the priorities of both the ICE and ICB Groups.

In the last two years, the ICE Group has carried out studies on a number of infectious agents, including HPV, hepatitis B and C viruses, human immunodeficiency virus, different types of human herpes virus and Helicobacter pylori in different cancer sites. New surveys of the prevalence of HPV infection in women with and without cervical cancer have recently acquired greater importance as they are prerequisites for a rational implementation of vaccination programmes against HPV. Conversely, the ICB Group has engaged mainly in smaller-scale biological studies, the aim of which is to characterise the oncogenic properties of specific HPV types. These biological studies complement, in terms of mechanisms involved, the overwhelming epidemiological evidence on the role of certain HPV types in the aetiology of cervical cancer. They also allow for the identification of other HPV types (notably cutaneous types) that represent good candidate causes for cancer sites where a viral aetiology is plausible but not firmly established (e.g. nonmelanomatous skin cancer). The ICB Group has greatly contributed in the last two years to the elucidation of the cutaneous HPV types that can interfere with cellular machinery and established comparisons with what is already well known for oncogenic mucosal HPV types. Whereas the activities of the ICE and ICB Groups are largely independent, important points of convergence have been represented by innovative studies carried out jointly on differences not between HPV types, but between the variants in a single HPV type in respect to oncogenic potential. In fact, the study of variants represents an important new opportunity to revisit the vast collection of cervical samples accrued at IARC during more

than 20 years of work on the epidemiology of HPV infection worldwide. In addition, during the period it was under the umbrella of EBC, the NTH Group conducted a broad series of research projects on the role of dietary habits, metabolism and genetic variants in the aetiology of specific cancer sites, notably in cancers of the breast, colon and prostate, within the European Prospective Investigation into Cancer and nutrition (EPIC) cohort. The former TOB Group completed and published a first Tobacco Handbook, and held a meeting for the preparation of a second one, which is in production. A new Cancer and Biomarkers (HOC) Group has been proposed as an addition to the repertoire of the EBC, and is the process of being created. The EBC encourages every kind of exchange and collaboration, both formal and informal, and many inter- and intraCluster collaborations are now ongoing or in the planning phase. Most notably, ICE and ICB provide advice to the interCluster Liver Cancer Programme and IARC studies that are evaluating viruses (e.g. the role of HPV infection in cancer of the oral cavity and lung, in collaboration with GEC). The over 100 publications produced by the ICE and ICB Groups in 2006-2007 provide good evidence of the high productivity and width of topics and international collaborations entailed in projects coordinated by the EBC. Several successful grant applications in Europe and the United States also confirm the international recognition of the EBC cluster’s work in cancer epidemiology and biology.

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Infections and Cancer Biology Group (ICB) Head Dr Massimo Tommasino Scientists Dr Rosita Accardi Dr Véronique Bouvard (until September 2006) Dr Bakary Sylla Technical Assistant Ms Anne-Marie Aguelon Secretaries Ms Dominique Bouchard (until March 2006) Ms Sarah Somerville (March 2006-April 2007) Ms Annick Rivoire (from May 2007) Visiting scientists and postdoctoral fellows Dr Maria Gabriella Donà (March-April 2006) Dr Anne-Sophie Gabet (until February 2007)

Our research is currently focused on the epitheliotropic human papillomaviruses (HPV ). The HPV family comprises approximately 100 different types that have been subgrouped in different genera according to their genomic DNA sequence. In addition, HPVs can be subdivided into mucosal and cutaneous types based on their tissue tropism. Members of the genus alpha, referred to as mucosal high-risk HPV types, have been extensively studied and are now well established as the cause of cervical carcinomas, as well as a sub-set of anogenital and head and neck carcinomas. Functional studies of the mucosal highrisk HPV types have demonstrated that the products of two early (E) viral genes, E6 and E7, play a key role in the malignant 34

Prof. Nitin Gangane (MarchJune 2007) Dr Tarik Gheit (until June 2007) Dr Uzma Hasan Dr Ishrak Hussain Shiekh (until July 2007) Dr Noureen Khan (May-June 2007) Dr Ruchi Shukla (from May 2007) Dr Mariela Torrente (SeptemberOctober 2007) Dr Jiping Yue (from July 2007) Dr Claudia Zannetti (from January 2007) Students Mr Sidy Thierno Bah (FebruaryJuly 2006) Ms Angelica Bellopede (MayOctober 2006; January-June 2007) Ms Alexandra Biliato (MayOctober 2006) Ms Gaëlle Billoud (until June 2006) Mr François Bonnay (MayOctober 2007) Mr Alexandre Bouzekri (September 2006-March 2007) transformation of infected cells. Both viral proteins induce deregulation of cell cycle and apoptosis, telomerase dysfunctions and chromosomal instabilities. Despite the induction of these deleterious events, not all HPV infections progress into invasive cancers; instead, in the majority of the cases the infection is cleared by the immune system in a relatively short time. Persistence of the viral infection is an essential requirement for the development of invasive cancers. The group of cutaneous HPV types has been poorly characterised so far. Emerging evidence strongly suggests that a sub-group of cutaneous HPV types that belongs to the beta genus of the HPV phylogenetic tree is linked to human carcinogenesis. These were first isolated in

Ms Chiara Camillo (SeptemberOctober 2006) Ms Beatriz Campo (March 2006) Ms Agnese Collino ( JanuaryJune 2006) Ms Iris Cornet (from August 2007) Mr Wen Dong (until August 2006) Ms Ikbal Fathallah (from November 2005) Ms Marine Malfroy (MayOctober 2007) Ms Lida Mancilla Estacio (August-September 2006) Ms Mariam Mansour (until December 2006) Ms Charlotte Mignon (MayOctober 2006) Ms Célie Pimard (until July 2006) Ms Laurette Prely ( JanuaryMarch 2006) Ms Amandine Saulnier ( January-March 2007; from October 2007) Mr Sinto Sebastian (from May 2006) Mr Abdel Majid Touka (until March 2007) patients suffering from a rare autosomal recessive cancer-prone genetic disorder, epidermodysplasia verruciformis (EV), and are consistently detected in non-melanoma skin cancer (NMSC) of EV, as well as in immunocompromised and immunocompetent individuals. However, a direct role of the beta HPV types in cancer development remains to be proven. The main goal of our group is to establish causal roles of specific infectious agents in human cancer. Several complementary approaches are being pursued. Transforming properties of cutaneous HPV types Due to the high heterogeneity and ubiquity of cutaneous beta HPV types, epidemiological studies have thus far not

Infections and Cancer Biology Group

provided conclusive evidence of their direct role in the development of NMSC. Most importantly, it is not clear yet whether, within the vast group of the beta HPVs, specific types may display more transforming properties than others. Functional studies on the mucosal HPV types associated with cervical cancer have demonstrated that E6 and E7 have in vitro transforming properties tightly correlated with their carcinogenic role in vivo. Based on these findings, we have performed a detailed analysis of the in vitro properties of several cutaneous HPV types and identified a beta HPV (type 38) that displays a number of transforming properties in vitro and in a transgenic mouse model. Similarly to the mucosal high-risk HPV16 E7, HPV38 E7 binds to pRb and promotes its degradation. In addition, HPV38 alters the functions of p53, but with a different mechanism than HPV16. In fact, HPV38 promotes the accumulation of a specific phosphorylated form of p53, which in turn activates the transcription of ΔNp73, a potent antagonist of p53 functions. In agreement with the in vitro data, expression of HPV38 E6 and E7 in the skin of transgenic mice resulted in the accumulation of ΔNp73 and inactivation of p53. Consistently, exposing the epidermis of HPV38 E6/E7-transgenic mice to ultraviolet rays did not lead to the activation of the p53-regulated gene p21WAF1 and cell-cycle arrest. HPV38 E6/E7-transgenic mice developed skin hyperplasia/dysplasia during their lifespan without progression to malignant lesions; however, carcinogen treatments led to a high incidence of papillomas, keratoacanthomas and squamous-cell carcinomas in HPV38 E6/E7-transgenic mice compared with non-transgenic animals. Our findings pave the way for new biological and epidemiological studies aiming to assess the role of beta HPV types in NMSC and other epithelial tumours. Factors determining viral persistence and cancer development Persistence of HPV infection has a key role in cervical cancer development. HPV16 is more likely to persist and to cause progression into cervical intraepithelial 35

neoplasia (CIN) than other mucosal highrisk HPV types. Nucleic acid sequencing of HPV16 genomes has revealed the existence of numerous natural variants that differ up to 2% from the original European prototype sequence in the coding region, and/or up to 5% in the non-coding region. By using cross-sectional analyses of several European populations, we have previously shown that within the European lineage, the L83V E6 variant harbouring a nucleotide substitution at position 350 (HPV16 350G), alone or in combination with other polymorphisms, is more prevalent in cervical cancer than in CIN. To test the significance of HPV16 and its E6 variants as risk factors for viral persistence and progression to high-grade lesions, we performed a nested case-control study within a cohort study of more than 15 000 Caucasian French women. Three groups infected with high-risk HPV were compared: a) women who cleared infection, b) women whose infection persisted, and c) women who progressed into high-grade lesions. Women with persistent HPV infection and those who progressed into high-grade lesions were more likely to harbour HPV16 than other high-risk HPV types. Notably, especially elevated ORs of persistence and progression were found among women who harboured the HPV16 350G variant. Thus, HPV type and HPV16 variant appear to be risk factors for viral persistence and progression of infections into high-grade cervical lesions. To determine whether the ability of HPV16 to persist more than the other mucosal high-risk types is linked to its efficiency in evading the immune system, we have characterised the impact of several mucosal HPV types on innate immunity. We show for the first time that HPV16 interferes with innate immunity by affecting the expression of Toll-like receptors (TLRs). Infection of human primary keratinocytes with HPV16 E6 and E7 recombinant retroviruses inhibits TLR9 transcription and hence induces functional loss of TLR9-regulated pathways. Similar findings were achieved in HPV16-positive cancer-derived cell lines and primary cervical cancers, demonstrating that this event also occurs in vivo. Interestingly, E6 and E7 from the

low-risk HPV6 are unable to downregulate the TLR9 promoter. In addition, E6 and E7 from high-risk HPV18, which are known to persist less competently in the host than HPV16, have a reduced efficiency compared with HPV16 in inhibiting TLR9 transcription. Our findings reveal a novel mechanism used by HPV16 to suppress the host immune response by deregulating the TLR9 transcript, providing evidence that abolishing innate responses may be a crucial step involved in the carcinogenic events mediated by HPV. In future studies we plan to characterise the molecular mechanisms of HPV16 E6 and E7 in down-regulating TLR9. Determination of the prevalence of mucosal and/or cutaneous HPV types To facilitate the epidemiological studies aiming to determine the prevalence of different HPV types in human specimens, we have developed a one-shot method for the detection of all characterised beta and 19 mucosal high-risk HPV types. This assay combines two different techniques: multiplex PCR using HPV type-specific primer for amplification of each E7 gene, and array primer extension (APEX) for typing. This novel method has been validated using clinical samples, which were simultaneously analysed for the presence of HPV types by additional methods. The initial data show that our HPV detection method has higher sensitivity, specificity and reproducibility than the other tested assays. In collaboration with the Infections and Cancer Epidemiology Group and other external groups we have several ongoing epidemiological studies aimed at determining the prevalence of HPV infections in healthy and cancer tissues of different anatomical regions, e.g., skin, oesophagus and the oral cavity.

Additional future studies In collaboration with other groups at IARC, we have recently initiated new studies on hepatitis B virus and hepatitis C virus. In particular, we will be focusing on the characterisation of host and viral factors involved in chronic infections.

Epidemiology and Biology Cluster

The ICB Group is grateful to the following for their collaboration in its projects: Professor Lutz Gissmann, Dr Michael Pawlita, Dr Martin Muller, Dr Angel Alonso, DKFZ, Heidelberg, Germany Dr Anna Giuliano, Dr Dana Rollison, Tampa, FL, USA Dr Mario Sideri, Dr Massimiliano Cazzanica, Bernardo Bonaldi, Chiara Casadio, European Institute of Oncology, Milan, Italy Dr Thomas Iftner, Tübingen, Germany Dr Susanne Kruger-Kjaer, Danish Cancer Society, Copenhagen Dr Simone Ottonello, University of Parma, Italy Financial support from the following bodies is gratefully acknowledged: Association for International Cancer Research, UK Association pour la Recherche sur le Cancer, France European Commission, Brussels Ligue Nationale contre le Cancer, Comité de la Drôme, Comité du Rhône, Comité de Savoie, France Conseil Régional Rhône-Alpes, France Fundacio La Marato de TV3, Institut Catala d’Oncologia, Spain

Publications Accardi R, Dong W, Smet A, Cui R, Hautefeuille A, Gabet AS, Sylla BS, Gissmann L, Hainaut P and Tommasino M (2006). Skin human papillomavirus type 38 alters p53 functions by accumulation of ΔNp73. EMBO Rep; 7: 334-340. Ateenyi-Agaba C, Weiderpass E, Tommasino M, Smet A, Arslan A, Dai M, KatongoleMbidde E, Hainaut P, Snijders PJF and Franceschi S (2006). Papillomavirus infection in the conjunctiva of individuals with and without AIDS: An autopsy series from Uganda. Cancer Lett; 239: 98-102. Brizio C, Galluccio M, Wait R, Torchetti EM, Bafunno V, Accardi R, Gianazza E, Indiveri C and Barile M (2006). Over-expression in Escherichia coli and characterization of two recombinant isoforms and human FAD synthetase. Biochem Biophys Res Commun; 344: 1008-1016. Dai M, Zhang WD, Clifford GM, Gheit T, He BC, Michael KM, Waterboer T, Hainaut P, Tommasino M and Franceschi S (2007). Human papillomavirus infection among 100 oesophageal cancer cases in the People’s Republic of China. Int J Cancer; 121: 1396-1398. Gheit T, Billoud G, de Koning MNC, Gemignani F, Forslund O, Sylla BS, Vaccarella S, Franceschi S, Landi S, Quint WGV, Canzian F and Tommasino M (2007). Development of a sensitive and specific multiplex PCR method combined with DNA microarray primer extension to detect beta-papillomavirus types. J Clin Microbiol; 45: 2537-2544.

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Gheit T, Landi S, Gemignani F, Snijders PJF, Vaccarella S, Franceschi S, Canzian F and Tommasino M (2006). Development of a sensitive and specific assay combining multiplex PCR and DNA microarray primer extension to detect high-risk mucosal human papillomavirus types. J Clin Microbiol; 44: 2025-2031. Gheit T, Toscano Simoes R, Tommasino M, Donadi EA and Guimaraes Gonçalves MA (2006). HPV16 variants in squamous intraepithelial lesions in human immunodeficiency virus-negative and-positive Brazilian women. Viral Immunol; 19: 340-345. Grodzki M, Besson G, Clavel C, Arslan A, Franceschi S, Birembaut P, Tommasino M and Zehbe I (2006). Increased risk for cervical disease progression of French women infected with the human papillomavirus type 16 E6-350 G variant. Cancer Epidemiol Biomarkers Prev; 15: 820-822.

Cancer Lett; 245: 44-50. Lichtig H, Algrisi M, Botzer LE, Abadi T, Verbitzky Y, Jackman A, Tommasino M, Zehbe I and Sherman L (2006). HPV16 E6 natural variants exhibit different activities in functional assays relevant to the carcinogenic potential of E6. Virology; 350: 216-227. Mancini A, Borrelli A, Schiattarella A, Fasano S, Occhiello A, Pica A, Sehr P, Tommasino M, Nüesch JPF and Rommelaere J (2006). Tumor suppressive activity of a variant isoform of manganese superoxide dismutase released by a human liposarcoma cell line. Int J Cancer; 119: 932-943. Mansour M, Touka M, Hasan U, Bellopede A, Smet A, Accardi R, Gabet AS, Sylla BS and Tommasino M. E7 properties of mucosal human papillomavirus types 26, 53 and 66 correlate with their intermediate risk for cervical cancer development. Virology; in press.

Hasan UA, Bates E, Takeshita F, Biliato A, Accardi R, Bouvard V, Mansour M, Vincent I, Gissmann L, Iftner T, Sideri M, Stubenrauch F and Tommasino M (2007). TLR9 expression and function is abolished by the cervical cancerassociated human papillomavirus type 16. J Immunol; 178: 3186-3197.

Mansour M, Touka M, Malena A, Indiveri C, Dong W, Gionfriddo I, Accardi R, Paradiso A, Sylla BS, Gabet AS and Tommasino M (2007). Human papillomagvirus type 77 E7 protein is a weak deregulator of cell cycle. Cancer Lett; 246: 274-281.

Hasan UA, Caux C, Perrot I, Doffin AC, Menetrier-Caux C, Trinchieri G, Tommasino M and Vlach J (2007). Cell proliferation and survival induced by Toll-like receptors is antagonized by type I IFNs. Proc Natl Acad Sci USA; 104: 8047-8052.

Niu Y, Roy F, Saltel F, Andrieu-Soler C, Dong W, Chantegrel AL, Accardi R, Thépot A, Foiselle N, Tommasino M, Jurdic P and Sylla BS (2006). A nuclear export signal and phosphorylation regulate Dok1 subcellular localization and functions. Mol Cell Biol; 26: 4288-4301.

Lee S, Huang H, Niu Y, Tommasino M, Lenoir G and Sylla BS (2007). Dok1 expression and mutation in Burkitt’s lymphoma cell lines.

Infections and Cancer Epidemiology Group (ICE) Head Dr Silvia Franceschi Scientists Dr Gary Clifford Dr Min Dai Dr Hugo De Vuyst (from November 2006) Dr Maria Claudia Nascimento Dr Teresa Norat (until August 2006) Mr Martyn Plummer

Persistent infection with viruses, bacteria or parasites is a predominant cause of human cancer. The role of the Infections and Cancer Epidemiology (ICE) Group within the framework of the mission of the International Agency for Research on Cancer is to identify the epidemiological features of cancers associated with human papillomavirus (HPV), human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), Kaposi sarcoma-related herpes virus (KSHV ), hepatitis C virus (HCV), hepatitis B virus (HBV), Helicobacter (H) pylori, and other infections.

Dr Salvatore Vaccarella Technical Assistants Ms Annie Arslan Mr Didier Colin Secretaries Ms Sylvie Nouveau (from June 2007) Ms Trudy Perdrix-Thoma

HPV The study of HPV is the main focus of the ICE Group. The successful introduction of HPV vaccines and HPV-based testing presuppose accurate knowledge of the infection burden and type-specific distribution of HPVs in different parts of the world. In order to address this issue and fill knowledge gaps on this subject, for many years the ICE Group has carried out population-based HPV prevalence surveys among women with and without cervical cancer worldwide. These surveys make up a large group referred to as the IARC HPV Prevalence Surveys (IHPS), which now

Visiting scientists and postdoctoral fellows Dr Anna Barón (until December 2006) Dr Charles Hsu (until April 2006) Dr Ni Li (from November 2006) Dr Ahsan Raza (until September 2007) Students Ms Delphine Boulch (until April 2006)

number in the high teens, with over 17 surveys completed. Priority for new surveys carried out in 2006–2007 included areas at high risk for cervical cancer for which almost no information is available (e.g. Eastern Europe and Central Asia) and countries where enormous social changes and migration from rural to urban areas may entail a substantial increase of HPV infection among young women (e.g. China). Results from these studies have revealed an overall HPV prevalence in cancer-free women that varied from 1.3% in Spain to 35% in Mongolia. Intermediate-to-high HPV prevalence (in the 15–20% range) was disclosed not only in Latin America and India, but also in China—which has generally been classified as a low-risk area for cervical cancer—and Poland, the only country that we have studied so far in Eastern Europe. The most commonly identified HPV type, in either single- or multiple-type infections, was HPV16. Africa showed the highest prevalence for all HPV types and Europe the lowest, but the variation in HPV16 prevalence across continents was smaller than in high-risk types other than HPV16 and in low-risk types. In Asia, HPV58 and 52 are more frequently detected than elsewhere. Women’s age and lifetime number of sexual partners were by far the variables 37

Epidemiology and Biology Cluster

most strongly associated with HPV positivity, but the relationship with age varied substantially by study area. Along with the most common age pattern (i.e. early peak of HPV prevalence in young women), U-shaped (mainly in Latin America) and flat distributions (in Nigeria, China and India) were found. Several more new surveys on HPV prevalence are currently in the planning phase. As before, HPV DNA testing will be performed at Vrije University, Amsterdam, the Netherlands, and serological testing at the Deutsches Krebsforschungszentrum, Heidelberg, Germany. Priority will continue to be given to areas at high risk for cervical cancer where little or no information is available. Special efforts will be made to improve the participation of young women, especially in sub-Saharan Africa. The sampling of a larger number of young women will allow a better projection of the incidence of cervical cancer 20 to 30 years from now based on current HPV prevalence. It will also help address the question of the proper age window when a prophylactic vaccine may be most effective in developing countries. Finally, some specific studies will focus on HIV-positive women. In addition, during 2006–2007, the ICE Group completed an update of systematic reviews of all published studies with typespecific HPV prevalence data in cervical cancer biopsies and in HIV-positive women. These types of systematic reviews continue to be very useful to the field, and will therefore be periodically updated. In collaboration with the Cancer Epidemiology Unit of Cancer Research UK (Oxford, UK), published and unpublished data from etiological studies on cervical cancer have been combined in a collaborative reanalysis of HPV and cervical cancer for a critical evaluation of HPV co-factors. These pooled data have been reanalysed in order to investigate the role of different lifestyle factors. Some of these have been completed in 2006–2007 (smoking, reproductive factors, hormonal contraceptives), and others will follow in the years to come (e.g. sexual factors). In the future, in collaboration with the Infections and Cancer Biology Group, the oncogenic potential of HPV16 variants will be examined among HPV16-positive 38

women with and without cancer from the IHPS. HIV/AIDS The ICE Group has carried out studies of cancer excess in people with HIV/AIDS in Italy, Switzerland and Uganda, and contributed to defining the excess of Hodgkin lymphoma, liver cancer, skin cancer and cervical cancer. The introduction of highly active antiretroviral therapy after 1996 greatly decreased standard incidence ratios of Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL), but not of HPVassociated cancer and Hodgkin lymphoma. The ICE Group is now updating record linkage between the Italian AIDS Registry and 19 cancer registries, which cover 23% of the Italian population. By the end of 2007 it should be possible to link approximately 15 000 people with AIDS. The approximately 12 000 HIV-positive people enrolled in the Swiss HIV Cohort Study (SHCS) since 1988 also allow for record-linkage studies like the one described for Italy. Indeed, the ICE Group has been able to update record linkage in order to expand on data previously collected, notably on non-AIDS-defining cancer. However, the major strength of the SHCS is the availability of detailed clinical follow-up information and biological samples. For instance, the SHCS offers an ideal opportunity to study HCV-related lymphomagenesis because approximately 30% of cohort participants are co-infected with HCV and HIV. A nested case-control study was carried out to investigate the contribution of HCV and HBV in the etiology of NHL and Hodgkin lymphoma in HIV-positive individuals, and has revealed a lack of association. A future study is planned on KSHV in this population. HCV/HBV We combined information published worldwide on the seroprevalence of hepatitis B surface antigen (HBsAg) and antibodies against hepatitis C virus (antiHCV ) in 27 881 hepatocellular carcinomas (HCCs) from 90 studies. As expected, HBV infection was found substantially more often than HCV infection in HCC cases from the majority of Asian and African countries with

available data. Conversely, more HCC cases were found to be anti-HCV-positive than HBsAg-positive in Europe and in the United States, as was also the case in Japan, Pakistan and Mongolia. In some countries (i.e. China and Mongolia), more than 10% of HCC cases were co-infected with both hepatitis viruses. More than half of HCC cases were both HBsAg-negative and antiHCV-negative in the United States and some Northern European countries. Occult HBV infection seems to have little or no clinical significance, at least among immunocompetent individuals. Owing to the long latent period of HCC, seropositivity among HCC cases does not reflect the current importance of the two viruses in the relevant population but rather that of two or three decades earlier. H pylori H pylori infection is associated with the development of gastric cancer. Although infection with an H pylori strain containing the cagA (cytotoxin-associated) gene (a marker for a pathogenicity island) may increase the risk of atrophic gastritis and gastric cancer, the relationship of variants in pathogenic H pylori genes to the severity and progression of precancerous lesions is not well-defined. Gastric biopsy specimens were obtained at enrolment from 2145 participants in a chemoprevention trial in Tachira State, Venezuela and examined histologically to determine the severity of precancerous lesions. There was a strong association between cagA-positive H pylori infection and the severity of gastric precancerous lesions, but cagA-negative H pylori was associated only with chronic gastritis. Using individuals with normal mucosa or superficial gastritis as controls, the odds ratio for dysplasia was 15.5 (95% confidence interval [CI]=6.42– 37.2) in cagA-positive individuals compared with uninfected individuals, and 0.90 (95% CI=0.37–2.17) for individuals infected with cagA-negative H pylori compared to uninfected individuals. The association between H pylori and gastric carcinoma may have been previously underestimated due to the poor accuracy of serologic H pylori markers and lack of discrimination by cagA genotype.

Infections and Cancer Epidemiology Group

Other cancer sites A network of multicentre case-control studies has been active in Italy for the last 25 years and has adapted to the development of new hypotheses on the link between lifestyle and cancer. Recent studies, in collaboration with the Aviano Cancer Center, Aviano, Italy; the Mario Negri Institute for Pharmacological Research, Milan, Italy; and the National Tumor Institute “G. Pascale”, Naples, Italy, have focused on cancer of the prostate, kidney, endometrium, ovary and haemolymphopoietic neoplasias. Studies on hepatocellular

carcinoma and nasopharyngeal cancer are providing new insight into the interaction between viral infection, alcohol drinking and tobacco smoking. Statistical methods During the period 2006–2007 the ICE Group participated in the development of the Epi software package, which provides tools for epidemiologists in the R language. Facilities allowed by the package include: interval censored survival data, cohort studies with long-term follow-up on multiple time scales, and relative risk

estimates for risk factors with multiple levels using the method of floating absolute risk. The ICE Group has also developed software for the analysis of Bayesian hierarchical models using Markov Chain Monte Carlo simulation. This software has been used to analyse the short-term natural history of HPV infection. It also supports the development of new statistical methods for criticism of complex Bayesian models.

The ICE Group is grateful to the following for their collaboration in its projects: Dr Teresa Aguado, Dr Nathalie Broutet, World Health Organization, Geneva, Switzerland; Dr Cecily Banura, Makerere University, Kampala, Uganda; Ms Alicja Bardin, Dr Witold Zatonski, Maria Sklodowska Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland; Dr Valerie Beral, Cancer Research UK, Oxford, UK; Dr F. Xavier Bosch, Institut Català d’Oncologia, Barcelona, Spain; Dr Federico Canzian, Dr Michael Pawlita, Deutsches Krebsforschungszentrum, Heidelberg, Germany; Dr Bendix Carstensen, Steno Diabetes Centre, Copenhagen, Denmark; Dr Philip Castle, Dr Mark Schiffman, National Cancer Institute, Rockville, MD, USA; Dr Luigino Dal Maso, Dr Jerry Polesel, Dr Diego Serraino, Centro di Riferimento Oncologico di Aviano, Aviano, Italy; Dr Catherine de Martel, Dr Julie Parsonnet, Stanford University, Stanford, CA, USA; Dr Bolormaa Dondog, National Cancer Center of Mongolia, Ulaanbaatar, Mongolia; Dr Peter Erb, Institute for Medical Microbiology, University of Basel, Basel, Switzerland; Dr Catterina Ferreccio, Catholic University, Santiago, Chile; Dr Patrick Francioli, Dr Martin Rickenbach, Coordination and Data Center-Swiss HIV Cohort Study, Lausanne, Switzerland; Dr Lucien Frappart, Hôpital Edouard Herriot, Lyon, France; Dr Doudja Hammouda, Institut National de Santé Publique, Algiers, Algeria; Dr Isabelle Heard, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; Dr Balman Singh Karki, Dr Ang Tshering Sherpa, B.P. Koirala Memorial Cancer Hospital, Bharatpur, Chitwan, Nepal; Dr Ikuko Kato, Wayne University, Detroit, MI, USA; Dr Namory Keïta, Université de Conakry, Conakry, Guinea; Dr Nahid Khodakarami, Shahid Beheshti Medical University, Tehran, Iran; Dr Dimitri Kordzaya, Alexandre Natishvili Institute of Morphology, Tbilisi, Georgia; Dr Carlo La Vecchia, Dr Eva Negri, Mario Negri Pharmacological Research Institute, Milan, Italy; Dr Chris J.L.M. Meijer, Dr Peter J.F. Snijders, Vrije University Medical Center, Amsterdam, the Netherlands; Dr Manivasan Moodley , The University of KwaZulu Natal, Westville, South Africa; Dr Gathari Ndirangu, University of Nairobi, Nairobi, Kenya; Dr Julian Peto, London School of Hygiene and Tropical Medicine, London, UK; Dr You-Lin Qiao, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; Dr Wim Quint, Dr Leen Jan van Doorn, DDL Diagnostic Laboratory, Voorburg, the Netherlands; Dr Gianni Rezza, Istituto Superiore di Sanità, Rome, Italy; Dr Guglielmo Ronco, Unità di Epidemiologia dei Tumori, Turin, Italy; Dr Shershah Syed, Sindh Government Hospital, Karachi, Pakistan; Dr Sukhon Sukvirach, National Cancer Institute, Bangkok, Thailand; Dr Christian Trépo, INSERM Unité 27, Lyon, France; Dr Vivian Tsu, Program for Appropriate Technology in Health, Washington, USA; Dr Paolo Vineis, Imperial College, London, UK;

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Epidemiology and Biology Cluster

Dr Jorge Vivas, Cancer Control Center, San Cristobal, Venezuela; Dr Elisabete Weiderpass Vainio, Karolinska Institutet, Stockholm, Sweden. Financial support is gratefully acknowledged for 2006-2007: Association for International Cancer Research, UK, World Health Organization Bill & Melinda Gates Foundation, USA; Merck & Co, Inc., USA; Oncosuisse, Switzerland; Wayne State University, USA. Publications Aguilar LV, Lazcano-Ponce E, Vaccarella S, Cruz A, Hernández P, Smith JS, Muñoz N, Kornegay JR, Hernández-Avila M, Franceschi S (2006). Human papillomavirus in men: comparison of different genital sites. Sex Transm Infect; 82: 31-33. Ateenyi-Agaba C, Weiderpass E, Tommasino M, Smet A, Arslan A, Dai M, KatongoleMbidde E, Hainaut P, Snijders PJF, Franceschi S (2006). Papillomavirus infection in the conjunctiva of individuals with and without AIDS: an autopsy series from Uganda. Cancer Lett; 239: 98-102. Bosetti C, Bravi F, Talamini R, Parpinel M, Gnagnarella P, Negri E, Montella M, Lagiou P, Franceschi S, La Vecchia C (2007). Flavanoids and prostate cancer risk: a study in Italy. Nutr Cancer; 56: 123-127. Bosetti C, Negri E, Gallus S, Dal Maso L, Franceschi S, La Vecchia C (2006). Anthropometry and multiple myeloma. Epidemiology; 17: 340341. Bosetti C, Rossi M, McLaughlin JK, Negri E, Talamini R, Liagou P, Montella M, Ramazzotti V, Franceschi S, La Vecchia C (2007). Flavanoids and the risk of renal cell carcinoma. Cancer Epidemiol Biomarkers Prev; 16: 98-101. Bosetti C, Scotti L, Dal Maso L, Talamini R, Montella M, Negri E, Ramazzotti V, Franceschi S, La Vecchia C (2007). Micronutrients and the risk of renal cell cancer: a case-control study from Italy. Int J Cancer; 120: 892-896. Bosetti C, Scotti L, Negri E, Talamini R, Levi F, Franceschi S, Montella M, Giacosa A, La Vecchia C (2006). Benign ovarian cysts and breast cancer risk. Int J Cancer; 119: 1679-1682. Bosetti C, Talamini R, Negri E, Franceschi S, Montella M, La Vecchia C (2006). Aspirin and the risk of prostate cancer. Eur J Cancer Prev; 15: 43-45. Bravi F, Bosetti C, Dal Maso L, Talamini R, Montella M, Negri E, Ramazzotti V, Franceschi S, La Vecchia C (2006). Food groups and risk of benign prostatic hyperplasia. Urology; 67: 73-79.

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Bravi F, Bosetti C, Dal Maso L, Talamini R, Montella M, Negri E, Ramazzotti V, Franceschi S, La Vecchia C (2006). Macronutrients, fatty acids, cholestorol and the risk of benign prostatic hyperplasia. Urology; 67: 1205-1211. Bravi F, Bosetti C, Scotti L, Talamini R, Montella M, Ramazzotti V, Negri E, Franceschi S, La Vecchia C (2007). Food groups and renal cell carcinoma: a case-control study from Italy. Int J Cancer; 120: 681-685. Bravi F, Bosetti C, Tavani A, Bagnardi V, Gallus S, Negri E, Franceschi S, La Vecchia C (2007). Coffee drinking and hepatocellular carcinoma risk: a meta-analysis. Hepatology 46: 430-435 Bravi F, Scotti L, Bosetti C, Talamini R, Negri E, Montella M, Franceschi S, La Vecchia C (2006). Self-reported history of hypercholesterolaemia and gallstones and the risk of prostate cancer. Ann Oncol; 17: 1014-1017. Castellsagué X, Díaz M, de Sanjosé S, Muñoz N, Herrero R, Franceschi S, Peeling RW, Ashley R, Smith JS, Snijders PJF, Meijer CJLM, Bosch FX (2006). Worldwide human papillomavirus etiology of cervical adenocarcinoma and its cofactors: implications for screening and prevention. J Natl Cancer Inst; 98: 303-315. Chiaffarino F, Parazzini F, Bosetti C, Talamini R, Canzonieri V, Montella M, Ramazzotti V, Franceschi S, La Vecchia C (2007). Risk factors for ovarian cancer histotypes. Eur J Cancer; 43: 1208-1213. Clifford GM, Franceschi S. Immunity, infection and cancer (2007). Lancet; 370: 6-7. Clifford G, Franceschi S, Diaz M, Muñoz N, Lina Villa L (2006). Chapter 3: HPV type distribution in women with and without neoplastic diseases. Vaccine; 24 Suppl3: S26-S34. Clifford GM, Gonçalves MAG, Franceschi S, for the HPV and HIV Study Group (2006). Human papillomavirus types among women infected with HIV: a meta-analysis. AIDS; 20: 2337-2344. Clifford GM, Shin HR, Oh JK, Waterboer T, Ju YH, Vaccarella S, Quint W, Pawlita M, Franceschi S (2007). Serologic response to oncogenic human papillomavirus types in male and female university students in Busan, South

Korea. Cancer Epidemiol Biomarkers Prev; 16: 1874-1879. Cutts FT, Franceschi S, Goldie S, Castellsagué X, de Sanjosé S, Garnett G, Edmunds J, Claeys P, Goldenthal K, Harper D and Markowitz L (2007). Human papillomavirus and HPV vaccines: a review. WHO Bull; 85: 719-726. Dai M, Bao YP, Li N, Clifford GM, Vaccarella S, Snijders PJF, Huang RD, Sun LX, Meijer CJLM, Qiao YL, Franceschi S (2006). Human papillomavirus infection in Shanxi Province, People’s Republic of China: a population-based study. Br J Cancer; 95: 96-101. Dai M, Zhang WD, Clifford GM, Gheit T, He BC, Michael KM, Waterboer T, Hainaut P, Tommasino M, Franceschi S (2007). Human papillomavirus infection among 100 oesophageal cancer cases in the People’s Republic of China. Int J Cancer; 121: 1396-1398. Dal Maso L, Franceschi S (2006). Hepatitis C virus and risk of lymphoma and other lymphoid neoplasms: a meta analysis of epidemiologic studies. Cancer Epidemiol Biomarkers Prev; 15: 2078-2085. Dal Maso L, La Vecchia C, Augustin LSA, Mantzoros CS, Kendall CWC, Franceschi S (2007). Relationship between a wide range of alcohol consumptions, components of the insulin-like growth factor system and adiponectin. Eur J Clin Nutr; 61: 221-225. Dal Maso L, Zucchetto A, Tavani A, Montella M, Ramazzotti V, Polesel J, Bravi F, Talamini R, La Vecchia C, Franceschi S (2006). Lifetime occupational and recreational physical activity and risk of benign prostatic hyperplasia. Int J Cancer; 118: 2632-2635. Dal Maso L, Zucchetto A, Tavani A, Montella M, Ramazzotti V, Talamini R, Canzonieri V, Garbeglio A, Negri E, Tonini A, La Vecchia C, Franceschi S (2007). Renal cell cancer and body size at different ages: an Italian multicentre casecontrol study. Am J Epidemiol; 166: 582-591. De Vuyst H, Franceschi S (2007). Human papillomavirus vaccines in HIV-positive men and women. Curr Opin Oncol ;19: 470-475. de Sanjosé S, Diaz M, Castellsagué X, Clifford G, Bruni L, Muñoz N, Bosch FX (2007).

Infections and Cancer Epidemiology Group Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a meta-analysis. Lancet Infect Dis; 7: 453-459. de Souza VA, Sumita LM, Nascimento MC, Oliveira J, Mascheretti M, Quiroga M, Freire WS, Tateno A, Boulos M, Mayaud P, Pannuti CS (2007). Human Herpesvirus-8 Infection and Oral Shedding in Amerindian and NonAmerindian Populations in the Brazilian Amazon Region. J Infect Dis; 196: 844-852. Deandrea S, Bertuccio P, Chatenoud L, Franceschi S, Serraino D, La Vecchia C (2007). Reply to “Alcohol consumption and risk of Hodgkin’s lymphoma and multiple myeloma: a multicentre case-control study” by Gorini et al. Ann Oncol; 18: 1119-1121. Franceschi S, Dal Maso L, Suligoi B, Rezza G (2006). Evidence for lack of cervical cancer screening among HIV-positive women in Italy. Eur J Cancer Prev; 15: 554-556. Franceschi S, Herrero R, Clifford GM, Snijders PJF, Arslan A, Anh PTH, Bosch FX, Ferreccio C, Hieu NT, Lazcano-Ponce E, Matos E, Molano M, Qiao YL, Rajkumar R, Ronco G, de Sanjosé S, Shin HR, Sukvirach S, Thomas JO, Meijer CJLM, Muñoz N and the IARC HPV Prevalence Surveys Study Group (2006). Variations in the age-specific curves of human papillomavirus prevalence in women worldwide. Int J Cancer; 119: 2677-2684. Franceschi S, Jaffe H (2007). Cervical cancer screening of women living with HIV infection: a must in the era of antiretroviral therapy. Clin Infect Dis; 45: 510-513. Franceschi S, Montella M, Polesel J, La Vecchia C, Crispo A, Dal Maso L, Casarin P, Izzo F, Tommasi LG, Chemin I, Trépo C, Crovatto M, Talamini R (2006). Hepatitis viruses, alcohol, and tobacco use in the etiology of hepatocellular carcinoma in Italy. Cancer Epidemiology Biomarkers Prev; 15: 683-689. Franceschi S, Polesel J, Rickenbach M, Dal Maso L, Probst-Hensch NM, Fux C, Cavassini M, Hasse B, Kofler A, Ledergerber B, Erb P, Clifford GM and the Swiss HIV Cohort Study (2006). Hepatitis C virus and non-Hodgkin’s lymphoma: findings from the Swiss HIV Cohort Study. Br J Cancer; 95: 1598-1602. Franceschi S, Smith JS, van den Brule A, Herrero R, Arslan A, Anh PTH, Bosch FX, Hieu NT, Matos E, Posso H, Qiao YL, Shin HR, Sukvirach S, Thomas JO, Snijders PJF, Muñoz N, Meijer CJLM (2007). Cervical infection with Chlamydia trachomatis and Neisseria gonorrhoeae in women from ten areas in four continents: a cross-sectional study. Sex Transm Dis; 34: 563-569. Galeone C, Pelucchi C, Levi F, Negri E, Franceschi S, Talamini R, Giacosa A, La Vecchia C

(2006). Onion and garlic use and human cancer. Am J Clin Nutr; 84: 1027-1032. Galeone C, Pelucchi C, Levi F, Negri E, Talamini R, Franceschi S, La Vecchia C (2006). Folate intake and squamous-cell carcinoma of the oesophagus in Italian and Swiss men. Ann Oncol; 17: 521-525. Galeone C, Pelucchi C, Talamini R, Negri E, Dal Maso L, Montella M, Ramazzotti V, Franceschi S, La Vecchia C (2007). Onion and garlic intake and the odds of benign prostatic hyperplasia. Urology; 70: 672-676. Galeone C, Pelucchi C, Talamini R, Negri E, Montella M, Ramazzotti V, Zucchetto A, Dal Maso L, Franceschi S, La Vecchia C (2007). Fibre intake and renal cell carcinoma: a case-control study from Italy. Int J Cancer; 121: 18691872. Galeone C, Talamini R, Levi F, Pelucchi C, Negri E, Giacosa A, Montella M, Franceschi S, La Vecchia C (2007). Fried foods, olive oil and colorectal cancer. Ann Oncol; 18: 36-39. Gallus S, Bravi F, Talamini R, Negri E, Montella M, Ramazzotti V, Franceschi S, Giacosa A, La Vecchia C (2006). Milk, dairy products and cancer risk (Italy). Cancer Causes Control; 17: 429437. Gallus S, Foschi R, Negri N, Talamini R, Franceschi S, Montella M, Ramazzotti V, Tavani A, Dal Maso L, La Vecchia C. Dietary zinc and prostate cancer risk: a case-control study in Italy. Eur Urol; 52: 1052-1057 (2007) Gallus S, Scotti L, Negri E, Talamini R, Franceschi S, Montella M, Giacosa A, Dal Maso L, La Vecchia C (2007). Artificial sweeteners and cancer risk in a network of case-control studies. Ann Oncol; 18: 40-44. Gallus S, Scotti L, Talamini R, Franceschi S, Dal Maso L, Negri E, La Vecchia C (2007). Reply to: Alcohol consumption and ovarian cancer risk in a population-based case-control study by Peterson et al. Int J Cancer; 121: 2578-2579. Gallus S, Talamini R, Bosetti C, Negri E, Montella M, Franceschi S, Giacosa A, La Vecchia C (2006). Pizza consumption and the risk of breast, ovarian and prostate cancer. Eur J Cancer Prev; 15: 74-76. Gallus S, Talamini R, Fernandez E, Dal Maso L, Franceschi S, La Vecchia C (2006). RE: Carbonated soft drink consumption and risk of espohageal adenocarcinoma. J Natl Cancer Inst; 98: 645-646. Garavello W, Bosetti C, Gallus S, Dal Maso L, Negri E, Franceschi S, La Vecchia C (2006). Type of alcoholic beverage and the risk of laryngeal cancer. Eur J Cancer Prev; 15: 69-73.

Garavello W, Randi G, Bosetti C, Dal Maso L, Negri E, Barzan L, Franceschi S, La Vecchia C (2006). Body size and laryngeal cancer risk. Ann Oncol; 17: 1459-1463. Garavello W, Rossi M, McLaughlin JK, Bosetti C, Negri E, Lagiou P, Talamini R, Franceschi S, Parpinel M, Dal Maso L, La Vecchia C (2007). Flavonoids and laryngeal cancer risk in Italy. Ann Oncol; 18: 1104-1109. Gheit T, Billoud G, de Koning MNC, Gemignani F, Forslund O, Sylla BS, Vaccarella S, Franceschi S, Landi S, Quint WGV, Canzian F, Tommasino M (2007). Development of a sensitive and specific multiplex PCR method combined with DNA microarray primer extension to detect beta-papillomavirus types. J Clin Microbiol; 45: 2537-2544. Gheit T, Landi S, Gemignani F, Snijders PJF, Vaccarella S, Franceschi S, Canzian F, Tommasino M (2006). Development of a sensitive and specific assay combining multiplex PCR and DNA microarray prmer extension to detect high-risk mucosal human papillomavirus types. J Clin Microbiol; 44: 2025-2031. Grodzki M, Besson G, Clavel C, Arslan A, Franceschi S, Birembaut P, Tommasino M, Zehbe I (2006). Increased risk for cervical disease progression of French women infected with the human papillomavirus type 16 E6-305G variant. Cancer Epidemiology Biomarkers Prev; 15: 820822. Hashibe M, Brennan P, Benhamou S, Castellsagué X, Chen C, Curado MP, Dal Maso L, Daudt AW, Fabianova E, Wünsch-Filho V, Franceschi S, Hayes R, Herrero R, Koifman S, La Vecchia C, Lazarus P, Levi F, Mates D, Matos E, Menezes A, Muscat J, Eluf-Neto J, Olshan AF, Rudnai P, Schwartz SM, Smith E, Sturgis EM, Szeszenia-Dabrowska N, Talamini R, Wei Q, Winn DM, Zaridze D, Zatonski W, Zhang ZF, Berthiller J, Boffetta P (2007). Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology consortium. J Natl Cancer Inst; 99: 777-789. Hildesheim A, Markowitz L, Hernandez Avila M, Franceschi S (2006). Chapter 27: Research needs following initial licensure of virus-like particle HPV vaccines. Vaccine; 24 Suppl3: S227S232. Homma T, Fukushima T, Vaccarella S, Yonekawa Y, Di Patre PL, Franceschi S, Ohgaki H (2006). Correlation between pathology, genotype and patient outcomes in glioblastoma. J Neuropathol Exp Neurol; 65: 846-854. International Collaboration of Epidemiological Studies of Cervical Cancer (Colin D, Franceschi S, Plummer M) (2006). Carcinoma of the cervix 41

Epidemiology and Biology Cluster and tobacco smoking: collaborative reanalysis of individual data on 13,541 women with carcinoma of the cervix and 23,017 women without carcinoma of the cervix from 23 epidemiological studies. Int J Cancer; 119: 1481-1495. International Collaboration of Epidemiological Studies of Cervical Cancer (Colin D, Franceschi S, Plummer M) (2006). Cervical carcinoma and reproductive factors: collaborative reanalysis of individual data on 16,563 women with cervical cancer and 33,542 women without cervical cancer from 25 epidemiological studies. Int J Cancer; 119: 1108-1124. International Collaboration of Epidemiological Studies of Cervical Cancer (Colin D, Franceschi S, Plummer M) (2007). Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: collaborative reanalysis of individual data on 8,097 women with squamous cell carcinoma and 1,374 women with adenocarcinoma from 12 epidemiological studies. Int J Cancer; 120: 885-891. International Collaboration of Epidemiological Studies of Cervical Cancer (Colin D, Franceschi S, Plummer M) (2007). Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies. Lancet; 370: 1609-1621. Karani A, De Vuyst H, Luchters S, Othigo J, Mandaliya K, Chersich MF, Temmerman M. The Pap smear for detection of bacterial vaginosis. Int J Gynecol Obstet 98: 20-23 (2007) Kato I, Canzian F, Franceschi S, Plummer M, van Doorn LJ, Lu Y, Gioia-Patricola L, Vivas J, Lopez G, Severson RK, Schwartz AG, Muñoz N (2006). Genetic polymorphisms in anti-inflammatory cytokine signaling and the prevalence of gastric precancerous lesions in Venezuela. Cancer Causes Control; 17: 1183-1191. Kato I, Canzian F, Plummer M, Franceschi S, van Doorn LJ, Vivas J, Lopez G, Lu Y, GioiaPatricola L, Severson RK, Schwartz AG, Muñoz N (2007). Polymorphisms in genes related to bacterial lipopolysaccharide/peptidoglycan signaling and gastric precancerous lesions in a population at high risk for gastric cancer. Dig Dis Sci; 52: 254-261. Kato I, van Doorn LJ, Canzian F, Plummer M, Franceschi S, Vivas J, Lopez G, Lu Y, GioiaPatricola L, Severson RK, Schwartz AG, Muñoz N (2006). Host-bacterial interaction in the development of gastric precancersous lesions in a high-risk population for gastric cancer in Venezuela. Int J Cancer; 119: 1666-1671. Kreimer AR, Randi G, Herrero R, Castellsagué X, La Vecchia C and Franceschi S, for the IARC Multicenter Oral Cancer Study Group (2006).

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Diet and body mass, and oral and oropharyngeal squamous cell carcinomas: analysis from the IARC multinational case-control study. Int J Cancer; 119: 2293-2297. Lambert R, Franceschi S (2007). Hepatocellular carcinoma. World Gastroenterology News 12: 2329. Li LK, Dai M, Clifford GM, Yao WQ, Arslan A, Li N, Shi JF, Snijders PJF, Meijer CJLM, Qiao YL, Franceschi S (2006). Human papillomavirus infection in Shenyang City, People’s Republic of China: a population-based study. Br J Cancer; 95: 1593-1597. Lim MK, Ju YH, Franceschi S, Oh JK, Kong HJ, Hwang SS, Park SK, Cho SI, Sohn WM, Kim DI, Yoo KY, Hong ST, Shin HR (2006). Clonorchis sinensis infection and increasing risk of cholangiocarcinoma in the Republic of Korea. Am J Trop Med Hyg; 75: 93-96. Lucenteforte E, Bosetti C, Talamini R, Montella M, Zucchetto A, Pelucchi C, Franceschi S, Negri E, Levi F, La Vecchia C. Diabetes and endometrial cancer: effect modification by body weight, physical activity and hypertension. Br J Cancer 97: 995-998 (2007) Montella M, Dal Maso L, Crispo A, Talamini R, Bidoli E, Grimaldi M, Giudice A, Pinto A, Franceschi S (2006). Do childhood diseases affect NHL and HL risk? A case-control study from northern and southern Italy. Leuk Res; 30: 917-922. Montella M, Polesel J, La Vecchia C, Dal Maso L, Crispo A, Crovatto M, Casarin P, Izzo F, Tommasi LG, Talamini R, Franceschi S (2007). Coffee and tea consumption and risk of hepatocellular carcinoma in Italy. Int J Cancer; 120: 1555-1559. Murri R, Franceschi S, Ravizza M, Fiore S, Bini T, Mussini C, Fasolo M, Liuzzi G, Ippolito G, D’Arminio Monforte A (2006). Access to gynecological services and Papanicolau tests in HIVinfected Italian women: a questionnaire survey. AIDS Care; 18: 376-378. Nascimento MC, de Souza VA, Sumita LM, Freire W, Munoz F, Kim J, Pannuti CS, Mayaud P (2007). Comparative study of Kaposi’s sarcoma-associated herpesvirus serological assays using clinically and serologically defined reference standards and latent class analysis. J Clin Microbiol; 45: 715-720. Nascimento MC, Ferreira S, Sabino E, Hamilton I, Parry J, Pannuti CS, Mayaud P (2007). Performance of the HerpeSelect (Focus) and Kalon enzyme-linked immunosorbent assays for detection of antibodies against herpes simplex virus type 2 by use of monoclonal antibodyblocking enzyme immunoassay and clinicovirological reference standards in Brazil. J Clin Microbiol; 45: 2309-2311.

Negri E, Bertuccio P, Talamini R, Franceschi S, Montella M, Giacosa A, Pelucchi C, La Vecchia C (2006). A history of cancer in the husband does not increase the risk of breast cancer. Int J Cancer; 118: 3177-3179. Negri E, Foschi R, Talamini R, Montella M, Ramazzotti V, Dal Maso L, Bosetti C, Franceschi S, Zucchetto A, La Vecchia C (2006). Family history of cancer and the risk of renal cell cancer. Cancer Epidemiol Biomarkers Prev; 15: 24412444. Negri E, Talamini R, Bosetti C, Montella M, Franceschi S, La Vecchia C (2006). Risk of prostate cancer in men who are childless. Int J Cancer; 118: 786-787. Negri E, Talamini R, Montella M, Dal Maso L, Crispo A, Spina M, La Vecchia C, Franceschi S (2006). Family history of hemolymphopoietic and other cancers and risk of non-Hodgkin’s lymphoma. Cancer Epidemiol Biomarkers Prev; 15: 245-250. Pelucchi C, Galeone C, Dal Maso L, Talamini R, Montella M, Ramazzotti V, Negri E, Franceschi S, La Vecchia C (2007). Dietary acrylamide and renal cell cancer. Int J Cancer; 120: 13761377. Pelucchi C, Galeone C, Levi F, Negri E, Franceschi S, Talamini R, Bosetti C, Giacosa A, La Vecchia C (2006). Dietary acrylamide and human cancer. Int J Cancer; 118: 467-471. Pelucchi C, Galeone C, Talamini R, Bosetti C, Montella M, Negri E, Franceschi S, La Vecchia C (2007). Lifetime ovulatory cycles and ovarian cancer risk in 2 Italian case-control studies. Am J Obstet Gynecol; 196: 83.e1-83.e7. Pelucchi C, Talamini R, Negri E, Franceschi S, La Vecchia C (2006). Genital and urinary tract diseases and prostate cancer risk. Eur J Cancer Prev; 15: 254-257. Plummer M (2006). Comment on article by Celeux et al. Bayes Anal; 1: 681-686. Plummer M, Best N, Cowles K, Vines K (2006). CODA: Convergence diagnosis and output analysis for MCMC. R News; 6: 7-11. Plummer M, Schiffman M, Castle PE, Maucort-Boulch D, Wheeler CM, for the ALTS Group (2007). A two-year prospective study of human papillomavirus persistence among women with a cytological diagnosis of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion. J Infect Dis; 195: 1582-1589. Plummer M, van Doorn LJ, Franceschi S, Kleter B, Canzian F, Vivas J, Lopez G, Colin D, Muñoz N, Kato I (2007). Helicobacter pylori cytotoxinassociated genotype and gastric precancerous lesions. J Natl Cancer Inst; 99: 1328-1334.

Infections and Cancer Epidemiology Group Plummer M, Vivas J, Lopez G, Bravo JC, Peraza S, Carillo E, Cano E, Castro D, Andrade O, Sánchez V, Garcia R, Buiatti E, Aebischer C, Franceschi S, Oliver W, Muñoz N (2007). Chemoprevention of precancerous gastric lesions with antioxidant vitamin supplementation: a randomized trial in a high-risk population. J Natl Cancer Inst; 99:137-146. Polesel J, Dal Maso L, La Vecchia C, Montella M, Spina M, Crispo A, Talamini R, Franceschi S (2007). Dietary folate, alcohol consumption, and risk of non-Hodgkin lymphoma. Nutr Cancer; 57: 146-150. Polesel J, Talamini R, Montella M, Dal Maso L, Crovatto M, Parpinel M, Izzo F, Tommasi LG, Serraino D, La Vecchia C, Franceschi S (2007). Nutrients intake and the risk of hepatocellular carcinoma in Italy. Eur J Cancer; 43: 2381-2387. Polesel J, Talamini R, Montella M, Parpinel M, Dal Maso L, Crispo A, Crovatto M, Spina M, La Vecchia C, Franceschi S (2006). Linoleic acid, vitamin D and other nutrient intakes in the risk of non-Hodgkin lymphoma: an Italian case-control study. Ann Oncol; 17: 713-718. Randi G, Franceschi S, La Vecchia C (2006). Gallbladder cancer worldwide: geographical distribution and risk factors. Int J Cancer; 118: 15911602. Randi G, Pelucchi C, Gallus S, Parpinel M, Dal Maso L, Talamini R, Augustin LSA, Giacosa A, Montella M, Franceschi S, La Vecchia C (2007). Lipid, protein and carbohydrate intake in relation to body mass index: an Italian Study. Public Health Nutr; 10: 306-310. Randi G, Pelucchi C, Negri E, Talamini R, Galeone C, Franceschi S, La Vecchia C. Family history of urogenital cancers in patients with bladder, renal cell, and prostate cancers. Int J Cancer 121: 2748-2752 (2007) Randi G, Scotti L, Bosetti C, Talamini R, Negri E, Levi F, Franceschi S, La Vecchia C. Pipe smoking and cancers of the upper digestive tract. Int J Cancer 121: 2049-2051 (2007) Raza SA, Clifford GM, Franceschi S (2007). Worldwide variation in the relative importance of hepatitis B and C viruses in hepatocellular carcinoma: a systematic review. Br J Cancer; 96: 1127-1134. Rossi M, Garavello W, Talamini R, La Vecchia C, Franceschi S, Lagiou P, Zambon P, Dal Maso L, Bosetti C, Negri E (2007). Flavonoids and risk of squamous cell esophageal cancer. Int J Cancer; 120: 1560-1564. Rossi M, Negri E, Foschi R, Franceschi S, La Vecchia C (2007). Relation between goiter and autoimmune thyroid disease, and gastric cancer. Int J Cancer; 120: 951-952.

Rossi M, Negri E, Talamini R, Bosetti C, Parpinel M, Gnagnarella P, Franceschi S, Dal Maso L, Montella M, Giacosa A, La Vecchia C (2006). Flavonoids and colorectal cancer in Italy. Cancer Epidemiol Biomarkers Prev; 15: 1555-1558.

Tavani A, Zucchetto A, Dal Maso L, Montella M, Ramazzotti V, Talamini R, Franceschi S, La Vecchia C (2007). Lifetime physical activity and the risk of renal cell cancer. Int J Cancer; 120: 1977-1980.

Rossi M, Garavello W, Talamini R, Negri E, Bosetti C, Dal Maso L, Lagiou P, Tavani A, Polesel J, Barzan L, Ramazzotti V, Franceschi S, La Vecchia C (2007). Flavonoids and the risk of oral and pharyngeal cancer: a case-control study from Italy. Cancer Epidemiol Biomarkers Prev; 16: 1621-1625.

Vaccarella S, Franceschi S, Herrero R, Muñoz N, Snijders PJF, Clifford GM, Smith JS, LazcanoPonce E, Sukvirach S, Shin HR, de Sanjosé S, Molano M, Matos E, Ferreccio C, Anh PTH, Thomas JO, Meijer CJLM and the IARC HPV Prevalence Study Group (2006). Sexual behavior, condom use and human papillomavirus: pooled anlaysis of the IARC Human Papillomavirus Prevalence Surveys. Cancer Epidemiol Biomarkers Prev; 15: 326-333.

Scotti L, Tavani A, Bosetti C, Dal Maso L, Talamini R, Montella M, Franceschi S, La Vecchia C (2007). Diabetes and risk of non-Hodgkin lymphoma: a case-control study. Tumori; 93: 1-3. Serraino D, Piselli P, Busnach G, Burra P, Citterio F, Arbustini E, Baccarani U, De Juli E, Pozzetto U, Bellelli S, Polesel J, Pradier C, Dal Maso L, Angletti C, Carrieri MP, Rezza G, Franceschi S, for the Immunosuppression and Cancer Study Group. Risk of cancer following immunosuppression in organ transplant recipients and in HIV-positive individuals in southern Europe. Eur J Cancer 43: 2117-2123 (2007) Smith JS, Lindsay L, Hoots B, Keys J, Franceschi S, Winer R, Clifford GM (2007). Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a metaanalysis update. Int J Cancer; 121: 621-632. Talamini R, Polesel J, Montella M, Dal Maso L, Crispo A, Tommasi LG, Izzo F, Crovatto M, La Vecchia C, Franceschi S (2006). Food groups and risk of hepatocellular carcinoma: a multicenter case-control study in Italy. Int J Cancer; 119: 2916-2921. Talamini R, Polesel J, Montella M, Dal Maso L, Crovatto M, Crispo A, Spina M, Canzonieri V, La Vecchia C, Franceschi S (2006). Food groups and risk of non-Hodgkin lymphoma: a multicenter, case-control study in Italy. Int J Cancer; 118: 2871-2876. Tavani A, Bosetti C, Franceschi S, Talamini R, Negri E, La Vecchia C (2006). Occupational exposure to ultraviolet radiation and risk of nonHodgkin lymphoma. Eur J Cancer Prev; 15: 453-457. Tavani A, Giordano L, Gallus S, Talamini R, Franceschi S, Giacosa A, Montella M, La Vecchia C (2006). Consumption of sweet foods and breast cancer risk in Italy. Ann Oncol; 17: 341354. Tavani A, Longoni E, Bosetti C, Dal Maso L, Polesel J, Montella M, Ramazzotti V, Negri E, Franceschi S, La Vecchia C (2006). Intake of selected mictronutrients and the risk of surgically treated benign prostatic hyperplasia: a case-control study from Italy. Eur Urol; 50: 549-554.

Vaccarella S, Herrero R, Dai M, Snijders PJF, Meijer CJLM, Thomas JO, Anh PTH, Ferreccio C, Matos E, Posso H, de Sanjosé S, Shin HR, Sukvirach S, Lazcano-Ponce E, Ronco G, Rajkumar R, Qiao YL, Muñoz N, Franceschi S and the IARC HPV Prevalence Surveys Study Group (2006). Reproductive factors, oral contraceptive use and human papillomavirus infection: pooled analysis of the IARC HPV Prevalence Surveys. Cancer Epidemiol Biomarkers Prev; 15: 2148-2153. Vaccarella S, Lazcano-Ponce E, Castro-Garduño JA, Cruz-Valdez A, Díaz V, Schiavon R, Hernández P, Kornegay JR, Hernández-Avila M, Franceschi S (2006). Prevalence and determinants of human papillomavirus infection in men attending vasectomy clinics in Mexico. Int J Cancer; 119: 1934-1939. Wang SS, Slager SL, Brennan P, Holly EA, De Sanjosé S, Bernstein L, Boffetta P, Cerhan JR, Maynadie M, Spinelli J, Chiu BCH, Cocco PL, Mensah F, Zhang Y, Nieters A, Dal Maso L, Bracci PM, Seniori Costantini A, Vineis P, Severson RK, Roman E, Cozen W, Weisenberger D, Davis S, Franceschi S, La Vecchia C, Foretova L, Becker N, Staines A, Vornanen M, Zheng T, Hartge P (2007). Family history of hematopoietic malignancies and risk of non-Hodgkin lymphoma (NHL): a pooled analysis of 10 211 cases and 11 905 controls from the International Lymphoma Epidemiology Consortium (InterLymph). Blood; 109: 3479-3488. Wu RF, Dai M, Qiao YL, Clifford GM, Liu ZH, Arslan A, Li N, Shi JF, Snijders PJF, Meijer CJLM, Franceschi S (2007). Human papillomavirus infection in women in Shenzhen City, People’s Republic of China, a population typical of recent Chinese urbanisation. Int J Cancer; 212: 1306-1311. Zucchetto A, Dal Maso L, Tavani A, Montella M, Ramazzotti V, Talamini R, Canzonieri V, Garbeglio A, Negri E, Franceschi S, La Vecchia C (2007). History of treated hypertension and diabetes mellitus and risk of renal cell cancer. Ann Oncol; 18: 596-600. 43

Molecular Carcinogenesis Cluster (MCC) Cluster Coordinator: Dr Pierre Hainaut

The Molecular Carcinogenesis Cluster (MCC) bridges laboratory-based molecular research with various important aspects of epidemiological and publichealth research conducted at IARC. It includes the Carcinogen Identification and Evaluation (CIE) Group, the Molecular Carcinogenesis Group (MOC), the Epigenetics Group (EGE) and includes a series of laboratory service activities, among them the IARC Biological Resource Centre (BRC). The main objective of the Cluster is to constitute a strong pool of expertise in carcinogenesis within IARC, involved in studies on biomarker discovery, assessment of function, validation and application to human subjects, including carcinogen identification and evaluation procedures. This approach explains the inclusion in the Cluster of the CIE Group, which develops the IARC Monographs series on the evaluation of carcinogenic risks to humans. At the same time, the Cluster has a clear focus on communication and cooperation with other Clusters and Groups, in particular through common technical platforms providing high-level service activities. The Cluster’s principal achievements over the past two years are the extension of the Cluster’s focus to include epigenetics, a major and rapidly developing field of research. Epigenetics focuses on stable changes in DNA and chromatin chemistry and structure that do not occur within the DNA sequence itself but are nevertheless essential for DNA replication, repair, expression or silencing during cell differentiation. Over the past few years, epigenetic changes have emerged as a driving force in carcinogenesis, on par with genetic modifications. In addition, epigenetic modifications may represent a 44

critical link between genes and environment in cancer causation. The need to master this critical area for research and translation led us to develop a new laboratory group, led by Dr Zdenko Herceg, to run original research projects as well as a service platform for the analysis of DNA methylation in molecular epidemiological studies. Since its establishment, the group has made a strong international impact through its own publications as well as through the development of an international network on Epigenetics and Cancer, which has held highly successful meetings at IARC in December 2006 and 2007. In addition to continuing its research activities on TP53 mutations and their interrelations with other genetic alterations in cancer of the breast, lung, oesophagus and liver, the Molecular Carcinogenesis Group has considerably expanded to provide a wide spectrum of technical services. The Group now runs a fully operational platform for mutation detection in cancer, with several collaborative projects both in-house as well as with a network of external collaborators. The main focus of many studies is on clinical trials in order to assess the prognostic and predictive value of mutations in breast, lung and liver cancer. Another critical development is the organisation of all human tissue collections at IARC into an integrated Biological Resource Centre. This centre manages specimens of over 1 million subjects and is one of the largest of its kind worldwide. The range of services provided by the BRC includes sample management, quality control, DNA extraction, aliquoting and analysis of several classes of biomarkers. Recently, the BRC has provided key contributions to international Genome-

Wide Association Studies (GWAS) on lung, kidney, pancreas, head and neck and other cancers. To assist collaborators and partners worldwide in developing highquality tissue and specimen collections, the BRC has coordinated an international workgroup who provided recommendations, guidelines and protocols on biobanking (available online at: http://www.iarc.fr/IARCPress/pdfs/standar dsBRC/index.php). The Carcinogen Identification and Evaluation Group is continuing its longrecognised task of reviewing carcinogenic exposures. Recent evaluations (documented in this report) have been developed according to the revised IARC monograph preamble, with greater focus on molecular and mechanistic information in the overall evaluation. All evaluations are now rapidly published (within 3 months of the evaluation meeting) as a summary publication in The Lancet Oncology, providing a rapid and effective source of information to the medical and scientific community at large. In 2008, the CIE group will undertake a major task: the development of a special initiative to mark the publication of Monograph 100, the 100th published volume of the IARC monographs series. This monograph will provide an extended review and reassessment of all evaluations carried out at IARC since the inception of the programme in 1972. This landmark publication will fulfil the ambition of the IARC Monographs programme to develop the “World Encyclopedia of Carcinogens”, in the footsteps of one of its main contributors, Dr Lorenzo Tomatis, who passed away in September 2007, and who has been, over the years, a leader in establishing and developing this programme.

Carcinogen Identification and Evaluation Group (CIE) Head Dr Vincent Cogliano Scientists Dr Andrea Altieri (through November 2007) Dr Robert Baan Dr Lamia Benbrahim-Tallaa (since September 2007)

The first step in cancer prevention is to identify the causes of human cancer. The Carcinogen Identification and Evaluation Group (CIE) produces the IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, a series of scientific reviews that since 1971 has evaluated more than 900 agents and identified more than 400 of these as carcinogenic, probably carcinogenic or possibly carcinogenic to humans. During

Dr Véronique Bouvard Dr Fatiha El Ghissassi Dr Yann Grosse Dr Béatrice Secretan Dr Kurt Straif

Mrs Jane Mitchell (through October 2007) Secretary Mrs Helene Lorenzen-Augros

Technical Assistants Mrs Sandrine Egraz Mrs Martine Lézère

2007, IARC convened Working Groups to develop three new volumes of IARC Monographs. Topics for these volumes had been recommended as high priorities by recent Advisory Groups. Volume 96: Alcoholic beverage consumption and ethyl carbamate (urethane) Worldwide, nearly 2 billion adults are regular consumers of alcoholic beverages,

with an average daily consumption of 13 g of ethanol (about one drink). Although moderate alcohol consumption has some health benefits, WHO has identified alcohol consumption as one of the top 10 risks in terms of the global burden of disease. Alcoholic beverages have long been known to cause cancer of the oral cavity, pharynx, larynx, oesophagus, and liver. This new evaluation added breast cancer and colorectal cancer, two of the most common

45

Molecular Carcinogenesis Cluster

cancers worldwide, to the list of cancers causally related to alcohol consumption. This suggests that the proportion of cancers attributable to alcohol consumption is higher than was previously estimated. Because these associations were generally noted with different types of alcoholic beverage, and in view of the carcinogenicity of ethanol in experimental animals, some of these risks can be attributed to ethanol itself. There was also substantial mechanistic evidence in humans to indicate that acetaldehyde derived from the metabolism of ethanol in alcoholic beverages contributes to causing malignant oesophageal tumours. A Working Group of 26 scientists from 15 countries met in February 2007 to critically review the pertinent scientific literature and develop the following evaluations: Alcoholic beverages: Carcinogenic to humans (Group 1) Ethanol in alcoholic beverages: Carcinogenic to humans (Group 1) Ethyl carbamate (urethane): Probably carcinogenic (Group 2A) Volume 97: 1,3-Butadiene, ethylene oxide, and vinyl halides (vinyl fluoride, vinyl chloride, vinyl bromide) As significant new data become available on an agent for which a Monograph exists, a reevaluation may be made. 1,3-Butadiene narrowly missed being classified in Group 1 during its previous evaluation; ethylene oxide was the first agent classified in 46

Group 1 on the basis of strong mechanistic evidence in exposed humans, and vinyl chloride has been suspected of causing other human cancers in addition to angiosarcomas. In the time since the previous evaluations of these agents, significant new data have become available. A working group of 21 scientists from 8 countries met in June 2007 to critically review the pertinent scientific literature and develop the following evaluations: 1,3-Butadiene (Group 1) Ethylene oxide (Group 1) Vinyl chloride (Group 1) Vinyl fluoride (Group 2A) Vinyl bromide (Group 2A)

Carcinogenic to humans Carcinogenic to humans

Another occupational exposure, painting, can result in exposure to many chemical pigments, solvents, and additives. Painters can also be exposed to other workplace hazards such as asbestos and crystalline silica. Epidemiological studies of painters have shown consistent increases in lung cancer and bladder cancer. In addition, there is some evidence of childhood leukaemia associated with maternal exposure to paint. A third occupational group, firefighters, are exposed to numerous toxic chemicals, including many known or suspected carcinogens. These intermittent exposures can be intense, and short-term exposure levels can be high for respirable particulate matter and for some carcinogens, notably benzene, benzo[a]pyrene, 1,3-butadiene and formaldehyde. Epidemiological studies suggest some potential for an increased cancer risk, but consistent patterns are difficult to discern due to the large variations in exposure across different fires and different groups of fire-fighters. A Working Group of 24 scientists from 10 countries met in October 2007 to critically review the pertinent scientific literature and develop the following evaluations:

Carcinogenic to humans Probably carcinogenic

Shift-work that involves circadian disruption: Probably carcinogenic (Group 2A)

Probably carcinogenic

Volume 98: Shift-work, painting, and fire-fighting Nearly 20% of the working population in Europe and North America engages in shift-work, which is most prevalent in the healthcare, industrial, manufacturing, mining, transport, communication, leisure, and hospitality sectors. Among the many different patterns of shift-work, those that include night work are most disruptive for the circadian clock. Epidemiological studies in a limited range of occupations have found that night work can increase the risk of cancer, and experimental studies have shown that the disrupting the circadian system can induce tumour development.

Occupational exposure as a painter: Carcinogenic to humans (Group 1) Occupational exposure as a fire-fighter: Possibly carcinogenic (Group 1) In addition, CIE began preparations for convening six meetings to prepare Volume 100 of the IARC Monographs. This milestone volume will review the human carcinogens identified to date. This information will then be used to develop two related scientific publications on tumour-site concordance between humans and experimental animals and on mechanisms involved in human carcinogenesis. For more information: http://monographs.iarc.fr/

Carcinogen Identification and Evaluation Group

Financial support from the following bodies is gratefully acknowledged: National Cancer Institute, USA; Center for Disease Control and Prevention/National Institute for Occupational Safety and Health, USA; National Institute of Environmental Health Sciences, USA, European Commission

Publications Peer-reviewed journals Altieri A, Hemmini K (2007). Number of siblings and the risk of solid tumours: a nationwide study. Br J Cancer 96: 1755-1759. Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, Cogliano V and the WHO International Agency for Research on Cancer Monograph Working Group (2006). Carcinogenicity of carbon black, titanium dioxide, and talc. Lancet Oncol 7: 295-296. Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, Bouvard V, Altieri A, Cogliano V and the WHO International Agency for Research on Cancer Monograph Working Group (2007). Carcinogenicity of alcoholic beverages. Lancet Oncol 8: 292-293. Cogliano VJ (2006). International Agency for Research on Cancer (IARC (http://www.iarc.fr) [Web Watch]. Toxicol Pathol 34; 405-406. Cogliano VJ (2006). Use of carcinogenicity bioassays in the IARC monographs. Ann NY Acad Sci 1076: 592-600. de Vocht F, Huizer D, Prause M, Jakobsson K, Peplonska B, Straif K, Kromhout H (2006). Field comparison of inhalable aerosol samplers applied in the European rubber manufacturing industry. Int Arch Occup Environ Health 79: 621-629.

Dresler CM, Leon ME, Straif K, Baan R, Secretan B (2006). Reversal of risk upon quitting smoking. Lancet 368: 348-349. Försti A, Jin Q, Altieri A, Johansson R, Wagner K, Enquist K, Grzybowska E, Pamula J, Pekela W, Hallmans G, Lenner P, Hemminki K (2007). Polymorphisms in the KDR and POSTN genes: association with breast cancer susceptibility and prognosis. Breast Cancer Res Treat; 101: 83-93. Grosse Y, Baan R, Straif K, Secretan B, El Ghissassi F, Cogliano V on behalf of the WHO International Agency for Research on Cancer Monographs Working Group (2006). Carcinogenicity of nitrate, nitrite, and cyanobacterial toxins. Lancet Oncol 7: 628-629. Grosse Y, Baan R, Straif K, Secretan B, El Ghissassi F, Bouvard V, Altieri A, Cogliano V, on behalf of the WHO International Agency for Research on Cancer Monograph Working Group (2007). Carcinogenicity of 1,3butadiene, ethylene oxide, vinyl chloride, vinyl fluoride, and vinyl bromide. Lancet Oncol 8: 679-680. Lei H, Hemminki K, Altieri A, Johansson R, Enquist K, Hallmans G, Lenner P, Försti A (2007). Promoter polymorphisms in matrix metalloprotienases and their inhibitors: few associations with breast cancer susceptibility and progression. Breast Cancer Res Treat 103: 61-69. McGregor D, Bolt H, Cogliano V, Richter-

Reichhelm HB (2006). Formaldehyde and glutaraldehyde and nasal cytotoxicity: case study within the context of the 2006 IPCS human framework for the analysis of a cancer mode action for humans. Crit Rev Toxicol 36: 821-835. Stayner L, Bena J, Sasco AJ, Smith R, Steenland K, Kreuzer M, Straif K (2007). Lung cancer risk and workplace exposure to environmental tobacco smoke. Am J Public Health 97: 545-551. Straif K, Baan R, Cogliano V (2006). Butadiene or styrene or butadiene and styrene or else? Occ Env Med 63: 157-158. Straif K, Baan R, Grosse Y, Secretan B, El Ghissassi F, Cogliano V, on behalf of the WHO International Agency for Research on Cancer Monograph Working Group (2006). Carcinogenicity of household solid fuel combustion and of high-temperature frying. Lancet Oncol 7: 977-978. Subramaniam RP, White P, Cogliano VJ (2006). Comparison of cancer slope factors using different statistical approaches. Risk Anal 26: 825-830. The International Agency for Research on Cancer Working Group on artificial ultraviolet (UV) light and skin cancer (Secretan B) (2007). The association of use of sunbeds with cutaneous malignant melanoma and other skin cancers: A systematic review. Int J Cancer; 120: 1116-1122. Wellmann J, Weiland SK, Neiteler G, Klein G, Straif K (2006). Cancer mortality in German carbon black workers 1976-98. Occup Environ Med 63: 513-521.

Books IARC (2006) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 86, Cobalt in hard-metals and cobalt sulfate, gallium arsenide, indium phosphide and vanadium pentoxide. Geneva, WHO Press IARC (2006) IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 87, Lead and lead compounds. Geneva, WHO Press IARC (2006). IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol. 88, Formaldehyde, 2-butoxyethanol and propylene glycol mono-t-butyl ether. Geneva, WHO Press 47

Molecular Carcinogenesis and Biomarkers Group (MCB) Group Head Dr Pierre Hainaut Group and Cluster Secretary Mrs Michelle Wrisez Mechanisms of Carcinogenesis Team Team Leader Dr Pierre Hainaut Scientists Dr Magali Olivier Dr Eric Van Dyck (until August 2007) Dr Tarik Gheit ( July-October 2007) Visiting Scientists Dr Claude Caron de Fromentel Mrs Chiara Goudin Dr Sabine Roman Dr Gihan Hosny ( July-August 2007) Dr Emanuela Moraes Ribeiro PINTO (February-March 2007) Mrs Kirtika Patel (SeptemberOctober 2006) Postdoctoral Fellows Dr Reto Brem (until August 2006) Dr Isabelle Coste-Invernizzi (from November 2004) Dr Nazir Dar (Oct 2005-July 2006) Dr Jarkko Loikkanen (August 2006-July 2007) Dr Xiaoli Ma (from October 2006) Dr Audrey Petitjean (from November 2005) Dr Amelie Plymoth (from February 2007) Students Mr Dominique Bourgeon Mr Alexis Cortot (from November 2005)

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Ms Nathalia de Oliveira Meireles Costa ( June-Oct 2007) Ms Priscila Falagan-Lotsch (Oct 2006-Nov 2007) Ms Lynnette Fernandez (from Oct 2006) Mr Olivier Galy (until June 2006) Mr Jeremy Lambert (from July 2007) Ms Emilie Le Roux (until July 2007) Ms Virginie Marcel (from September 2004) Ms Lydia Messaoudi (until February 2007) Ms Mounia Mounawar Ms Edenir Palmero (April-July 2006) Ms Aurélia Petré Ms Hong Shi Ms Amélie Thépot (from Dec 2004) Ms Violaine Tribollet (Dec 2005Nov 2006) Ms Myriam Lereau (Feb-June 2006 & from September 2006) Mr Matthew J. Armstrong ( JulySeptember 2007) Trainees Ms Claire Bollart (May-October 2006) Ms Marie-Jennifer Carrillon (May-October 2007) Ms Sophie Desira (AprilAugust 2007) Ms Sophie Guillot (Oct-Nov 2006 & Jan-March 07) Ms Doriane Gouas (AprilMay 2006) Miss Géraldine Lathoud (MarchAugust 2006) Ms Véronique Massé (AprilAugust 2006) Mr Kevin Panhalleux ( JuneAugust 2007)

Ms Clara Ros (December 2006March 2007) Ms Amandine Saulnier ( JuneAug 2006) Ms Vineetha Vijayakumar (MayJuly 2007) Laboratory Technicians Mrs Agnès Hautefeuille Mrs Ghislaine Martel-Planche Laboratory Infrastructures & Resources Team Secretary Mrs Dominique Bouchard Scientist Dr Vladimir Krutovskikh Laboratory technicians Mrs Elodie Caboux Mrs Elodie Colney Mrs Marie-Pierre Cros Ms Brigitte Chapot Mr José Garcia Mr Christophe Lallemand Mr Thomas Cler Ms Béatrice Vozar Mrs Stéphanie Villar Laboratory Aides Mrs Marcelle Essertel Mrs Nicole Farina Ms Maria Maranhao Mrs Gertrude Tchoua

Molecular Carcinogenesis and Biology Group

Mutations in specific genes are the cornerstone of cancer. These mutations introduce irreversible changes in the programmes that run cell proliferation, differentiation and survival. Cancer occurs, develops and progresses through the accumulation of mutations that activate pathways promoting cell division while inactivating those that control cell life span and decreasing those that monitor the genetic integrity of the cell. Collectively, these mutations profoundly modify cell metabolism, shape, mobility and adaptability to adverse conditions, making it capable of malignant behaviour. Of about 300 genes that are recurrently altered in human cancer, the most frequently targeted by mutations is the tumour suppressor gene TP53. The product of this gene, the p53 protein, normally functions as an “emergency brake” that arrests the development or eliminates cells that have acquired potentially oncogenic defects. It thus acts as a rate-limiting event en route to full-blown cancer, and its inactivation, by direct mutation or by other molecular means to bypass its action, is mandatory for cancer to develop. Furthermore, the loss of p53 function makes cells prone to acquiring further genetic defects at an accelerated pace, increasing their capacity to adapt to multiple microenvironmental conditions and to resist the body’s defences as well as cancer treatment. The scientific strategy of the MCB group is to use the TP53 gene and its alterations as guides to explore in detail the mechanisms of carcinogenesis and to identify biomarkers useful for cancer prevention, early detection or therapy. Within the MCB group, the Mechanisms of Carcinogenesis team (MCA) develops research aimed at identifying when and why TP53 mutations occur in the temporal sequence of events leading to cancer, to understand their consequence on cell physiology and behaviour, to develop translational studies to apply this knowledge to the analysis of human specimens and to run large-scale studies aimed at assessing the significance of biomarkers in molecular epidemiology and pathology. Key to this strategy is the IARC TP53 mutation database, a public database that contains all TP53 mutations identified so far in cancer,

as well as detailed annotation on the pathologies in which they occur, the agents suspected to cause them, their structural and functional consequences on p53 protein functions, their association with patients’ clinical outcome and their concordance with other recurrent genetic or epigenetic alterations. This database is a service to the wider scientific and medical communities as well as a research instrument, not only for data mining, but for generating molecular information required to fill the gaps between different datasets (such as the analysis of the correlations between mutation effects on p53 protein structure, function, and clinical effects). In addition to research activities, the MCB group also runs a number of core scientific service activities. The team of Laboratory Infrastructures and Resources runs the IARC Biological Resource Centre, an integrated structure that handles all practical aspects of IARC human specimen biobanking activities. Other services include a central facility for cell biology, and the running of an integrated programme of biomarker development that involves several other groups across the IARC scientific structure. Key achievements in 2006-2007 In 2006-07, the Mechanisms of Carcinogenesis Team has concentrated its activities on the study of cancers of the liver, of the oesophagus, of the lung and of the breast, as well as to the understanding of the functional consequences of germline TP53 mutations, the inheritance of which underlines a panel of cancer predisposing familial syndromes collectively known as “Li-Fraumeni Syndrome”. Milestone achievements are: • The assessment of the prognostic value of TP53 mutations in breast cancer, demonstrating their usefulness as a biomarker in molecular pathology; • The identification of a specific functional pathway interconnecting mutations in the EGFR gene with TP53 mutations in lung cancers of never-smokers, supporting the notion that these cancers develop through mechanisms that are distinct from those involved in smokers; • The demonstration that aflatoxin, a common dietary mutagen that causes

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liver cancer in sub-Saharan Africa and parts of Asia, can induce TP53 mutations that are detectable in exposed subjects well ahead of cancer occurrence; The demonstration that biliary acid stress can cause downregulation of p63, a paralogue of p53 that is critical for squamous differentiation, providing a plausible mechanism for the switch in cell differentiation that causes intestinal metaplasia in the lower oesophagus (Barrett’s metaplasia); The identification of a particular, lowpenetrance germline TP53 mutation that is common in the general population of Southern Brazil and causes a complex cancer predispostion syndrome; The discovery of novel cross-talks between p53 and NFkappaB, a transcription factor involved in inflammation response, in the activation of cyclooxygenase 2 (Cox-2) in response to DNA damage, leading to a better understanding of the significance of elevated Cox-2 levels in oesophageal cancers; and The discovery of a regulatory GQuadruplex structure within a common polymorphic region of TP53 intron 3, which modulates mRNA splicing and controls the balance between p53 protein isoforms, in relation with genetic susceptibility to cancer.

The main activity in the Laboratory Infrastructures & Resources Team (LIR) has consisted in the building of a stable infrastructure and management mechanism for present and future human specimen collections by IARC scientists. In addition, the team has re-organised the tissue banking and specimen circulation logistics of the EPIC study. Overall, the IARC Biological Resource Centre hosts specimens from over 600 000 subjects (including EPIC). The team has also steered the work of an expert group and a public consultation process leading to the development of international minimum standards and protocols for Biological Resource Centres dedicated to cancer research.

49

Molecular Carcinogenesis Cluster

TP53 mutations as biomarkers of prognosis in breast cancer Despite many publications, the prognostic and predictive significance of TP53 mutation remains obscure. This is mainly due to poor study design, small and heterogenous case series and incomplete follow-up. To address these questions, we have assembled a cohort of close to 1800 patients with breast cancer with a median follow-up of 10 years, by pooling data and specimens from 12 European breast cancer cohorts. TP53 analysis in this cohort unambiguously demonstrates that mutation is a strong and independent marker of poor prognosis, in particular in tumours that retain estrogen/progesterone receptor (ER/PR) expression. Strikingly, TP53 mutation does not affect the prognosis of ER/PR negative tumours. These findings suggest that the response of breast cells to hormones (or to hormone withdrawal) involves the p53 protein. This hypothesis is currently being tested using cancer specimens from clinical trials in which patients have been randomly allocated to anti-hormone therapy plus or minus chemotherapy. In addition, experimental studies are in progress using cell cultures to identify how p53 may become recruited by the modulation of signalling pathways recruited by ER/PR. Mutation patterns in never-smokers In the past, the group has concentrated its effort on the identification of carcinogen mutational “fingerprints” in lung cancers of tobacco smokers. During the past two years, we have re-directed our activities on lung cancer of never-smokers, with the aim of understanding the mechanisms responsible for this increasing type of cancer. We found, as in many recent studies, that mutation of the EGF receptor gene (EGFR) was a common event in lung cancer of never-smokers. Furthermore, we found that EGFR mutation was systematically associated with functional inactivation of p53, either by mutation, or by loss of expression of p14Arf, a critical p53 regulator, or by both events simultaneously. This observation demonstrates that oncogenic stress by EGFR mutation (that is, the constitutive activation of growth promoting pathways) rather than genotoxic stress is causal in the 50

pathogenesis of lung cancer of neversmokers. EGFR mutation themselves may occur as the consequence of a selection process by which lung cells adapt to modifications of their microenvironment. Based on results reported earlier that show an unexpectedly high prevalence of intracellular markers of inflammation damage in lung cancer of never-smokers, we favour the hypothesis that a form of chronic inflammatory stress may be involved in the initial steps of lung carcinogenesis in never-smokers. Current studies are aimed at assessing these hypotheses, as well as the impact of TP53 mutations on lung cancer responses to chemotherapy and to drugs targeting activated EGFR.

Aflatoxin-induced mutations in liver cancer Aflatoxin is a common mutagen present in the staple diet in many tropical counties. When associated with chronic Hepatitis B virus carriage, exposure to aflatoxin has a multiplicative effect on the risk of hepatocellular carcinoma (HCC). Together, these two factors explain most of the burden of liver cancer in sub-Saharan Africa and in south-eastern Asia. In these regions, HCC often contains a special mutation at codon 249 in TP53 (Ser249). In parallel with our involvement in the Gambia Hepatitis Intervention Study, we have studied the occurrence of this mutation in a cohort of subjects exposed to aflatoxin in two rural communities in The Gambia. Using a highly sensitive mass spectrometry approach, we have shown that Ser249 could be detected in fragments of DNA that circulate in the plasma of patients without clinical symptoms of chronic liver disease. Levels of Ser249 were significantly higher in subjects who are chronic HB carriers than in non-carriers. Furthermore, Ser249 levels showed temporal variations that recapitulate the known seasonal variations in the level of exposure to aflatoxin. Together, these results show for the first time the detection of mutations in TP53 as a marker of ongoing exposure to an environmental mutagen. They support the notion that chronic HB carriers are at higher risk of acquiring the Ser249 mutation than non-carriers, providing an

explanation for the multiplicative effect observed in epidemiological studies. However, these results also suggest that monitoring Ser249 alone will not be predictive of the individual risk of HCC. Current studies are focusing on other mutation markers in plasma DNA (betaCatenin) as well as on in vitro studies using a cell line infectable by HBV to examine the molecular consequences of HBV replication on the cell responses to aflatoxin exposure. In parallel, other studies have addressed whether Ser249 may exert special functions in liver cells that could be targeted by inhibitory drugs, providing a preclinical paradigm for developing targeted, cheap therapies for patients in high-incidence area. Using RNA interference as a tool to switch off Ser249 expression in cancer cells, we found that the mutant was critical for maintaining a high DNA replication capacity in liver cancer cells expressing HBV antigens, and that a new candidate drug, PRIMA-1, could efficiently kill cells expressing Ser249. Current work addresses the biochemical mechanisms of PRIMA-1 action. P63 as a critical regulator of proliferation and differentiation in squamous oesophagus TP53 belongs to a gene family that also contains two other genes, TP73 and TP63.

Molecular Carcinogenesis and Biology Group

The latter is expressed` in a complex manner in the proliferating basal cells of squamous oesophagus and is often amplified and over-expressed in squamous cell carcinomas (SCC). In contrast, p63 expression is extremely low in oesophageal carcinoma. Experimental studies in mice have shown that disruption of TP63 impairs squamous cell differentiation and induces the oesophagus mucosa to develop as a monolayer of columnar cells. This structure is reminiscent of Barrett’s mucosa, a common metaplasia that develops in the lower third of the oesophagus in response to gastric reflux and is considered as precursor to ADC. We performed in vitro studies to assess the effect of bile acids on the expression of p63 in squamous cells. Results showed that, upon exposure to acid and bile salts, the p63 protein was rapidly degraded by proteolysis in the proteasome, and cells lost typical keratine differentiation markers. These results indicate that loss of p63 upon exposure to acid and bile stress may cause changes in the cell differentiation programme leading to intestinal metaplasia. Current studies focus on detecting p63 degradation in the squamous mucosa of subjects with chronic gastric reflux as an early marker of the formation of Barrett’s mucosa. A low-penetrance TP53 germline mutation in Brazilian families Inheritance of a TP53 mutation causes the Li-Fraumeni Syndrome (LFS), a familial disease of predisposition to multiple early cancers. Studies in south Brazil have shown that a mild version of this syndrome was much more common than expected in the Brazilian population. This is due to the high frequency in the Brazilian population of a rare TP53 allele that carries a single nucleotide variation at codon 337, leading to a substitution that alters p53 protein function in a conditional manner. In collaboration with the GCS group, we have shown that the presence of this variant is the consequence of a founder effect that took place in the 17th or 18th century and has affected up to 0.3% of the

population in the southern states of Brazil. The high frequency and low penetrance of this variation raises new challenges for the identification and management of subjects at risk of cancer. It is possible that such founder TP53 mutations may also exist in other populations, stressing the importance of developing an international network on LFS to help and support the identification of families with this syndrome in lowresource countries. Cross-talk between p53 and NFkappaB: role in inflammation damage Chronic inflammation is a common precursor condition in many cancers. We have identified a novel interconnection between inflammation response and mechanisms that regulate cell proliferation and apoptosis. We have shown that NFkappaB, one of the main regulators of inflammatory responses, could bind to p53 and mediate survival in cells exposed to DNA damage. This connection may be essential to explain how cells exposed to inflammatory damage may survive despite the formation of DNA lesions. The recruitment of NF-kappaB by p53 induces the expression of cyclooxygenase-2, a common occurrence in many solid tumours. This new connection provides a mechanism to understand the basis for deregulated Cox-2 expression in many tumours. Regulation of expression of p53 isoforms We recently identified a novel isoform of the p53 protein, called DeltaNp53, which lacks the N-terminus. This protein lacks transactivation capacity but binds DNA with high affinity. We have now identified the mechanism that regulates the expression of this protein. DeltaNp53 is assembled from an alternatively spliced RNA that retains intron 3. The retention of intron 3 is dependent upon the presence of a polymorphic structure in intron 3, a 16bp repeat that is present in about 20% of normal subjects. We have found that this structure folds into a G-quadruplex in p53 mRNA. G-quadruplexes are single-stranded DNA or mRNA loops stabilised by the binding of potassium ions on particular

arrangements of guanine. The levels of different isoforms of mRNA vary according to the presence and structure of these Gquadruplexes. The polymorphic character of this region may contribute to genetic susceptibility since subjects with different G-quadruplexes in p53 mRNA may express different levels of the p53 protein. TP53 Database The IARC TP53 Database (http://wwwp53.iarc.fr/) is a web resource dedicated to the compilation and analysis of TP53 mutations associated with human cancers and reported in the peer-reviewed literature. The database is updated once a year and the latest update (October 2007) includes more than 25 000 somatic and 400 germline mutations with related information on the biological activities of mutant proteins and on patient demographics, life-style, and clinical parameters. These data can be freely analysed and downloaded through a web interface. Current projects are focused on the characterisation of mutations phenotypes. Using the database, some bioinformatics approaches as well as mutation screening in original series of patients, we showed that mutagenesis and loss of transactivation activities are the main forces that shape TP53 mutation patterns in human cancers, that the phenotype of germline mutations is highly related to their transactivation capacity, and that TP53 mutation is an independent factor of poor prognosis in breast cancer, different types of mutations having a different prognostic value. Within a FP6 European network project on mutant p53 (http://www .mutp53.com/), we have also organized two events, the 3rd international workshop on mutant p53 combined with a symposium on the Li-Fraumeni syndrome (http:// wwwp53.iarc.fr/P53meeting2007/P53meet ing2007.html), and an inter-national training workshop on mutation databases in cancer (http://www.iarc.fr/-ENG/Training Courses/lyon2007_mutationsdb.php).

51

Molecular Carcinogeneis Cluster

The MCB Group is grateful to the following for their collaboration in its projects: Robert Walton, Sarah Rowland-Jones, Maimuna Mendy, Banjul, Republic of The Gambia Andrew Hall, London, UK, Simonetta Viviani, Ferney Voltaire, France, Maria-Isabel Achatz, Sao Paulo, Brazil, Hany Ariffin, Kuala Lumpur, Malaysia, Mariano Barbacid, Madrid, Spain, Anne-Lise Børresen-Dale, Oslo, Norway, Christian Brambilla, Grenoble, France, Elisabeth Brambilla, Grenoble, France, Sandy Dawsey, Washington DC, USA,Charles Dumontet, Lyon, France, John Field, Liverpool, UK, Claudia Gallo, Rio de Janeiro, Brazil, Gihan Hosny, Alexandria, Egypt, Stefano Landi, Pisa, Italy, M. Lathrop, Evry, France, Reza Malekzadeh, Tehran, Iran, Moshe Oren & Varda Rotter, Rehovat, Israel, Patricia Prolla, Porto Alegre, Brazil, Luis Felipe Pinto, Rio de Janeiro, Brazil, Alain Puisieux, Lyon, France, Petcharin Srivatanakul, Bangkok, Thailand, Jean-Yves Scoazec, Lyon, France, Galina Selivanova, Stockholm, Sweden, Claude Sardet & Laurent le Cam, Montpellier, France, Jean-Claude Soria, Villejuif, France, Christian Trepo, Lyon, France, Paolo Vineis, London, UK, Giuseppe Viale, Milan, Italy, Klas Wiman, Stockholm, Sweden, Kurt Zatloukal, Graz, Austria

Financial support from the following bodies is gratefully acknowledged: Association pour la Recherche sur le Cancer, France, Association for International Cancer Research, UK, Canceropôle CLARA, France, Comité contre les Maladies Repiratoires, France, European Commission, Institut National du Cancer, France, Ligue Nationale Contre le Cancer, Comité de Savoie, France, Ligue Nationale Contre le Cancer, Comité de Saône et Loire, Ligue Nationale Contre le Cancer, Comité de la Drôme, France, Ligue Nationale Contre le Cancer, Comité du Rhône, France, Ligue Nationale Contre le Cancer, France,

Publications Journals Accardi R, Dong W, Smet A, Cui R, Hautefeuille A, Gabet AS, Sylla BS, Gissmann L, Hainaut P, Tommasino M (2006). Skin human papillomavirus type 38 alters p53 functions by accumulation of deltaNp73. EMBO Rep 7: 334340. Achatz MI, Olivier M, Calvez FL, MartelPlanche G, Lopes A, Rossi BM, Ashton-Prolla P, Vargas FR, Casali da Rocha JC, Vettore AL, Hainaut P (2007). Response to “Germline TP53 R337H mutation is not sufficient to establish LiFraumeni or Li-Fraumeni-like syndrome”, by Ribeiro et al. Cancer Lett 247: 356-358. Achatz MI, Olivier M, Le Calvez F, MartelPlanche G, Lopes A, Rossi BM, Ashton-Prolla P, Giugliani R, Palmero EI, Vargas FR, Da Rocha JC, Vettore AL, Hainaut P (2007). The TP53 mutation, R337H, is associated with LiFraumeni and Li-Fraumeni-like syndromes in Brazilian families. Cancer Lett 245: 96-102. Aranda M, Gonzalez-Nilo F, Riadi G, Díaz V, Perez J, Martel G, Hainaut P, Mimbacas A (2007). Loss of TP53-DNA interaction induced by p.C135R in lung cancer. Oncol Rep 18(5):1213-1217. 52

Ateenyi-Agaba C, Weiderpass E, Tommasino M, Smet A, Arslan A, Dai M, KatongoleMbidde E, Hainaut P, Snijders PJ, Franceschi S (2006) Papillomavirus infection in the conjunctiva of individuals with and without AIDS: an autopsy series from Uganda. Cancer Lett 239: 98102. Benoit V, de Moraes E, Dar NA, Taranchon E, Bours V, Hautefeuille A, Taniere P, Chariot A, Scoazec JY, Moura Gallo CV, Merville MP, Hainaut P (2006) Transcriptional activation of cyclooxygenase-2 by tumor suppressor p53 requires nuclear factor-kappaB. Oncogene 25: 57085718. Boonstra JJ, van der Velden AW, Beerens EC, van Marion R, Morita-Fujimura Y, Matsui Y, Nishihira T, Tselepis C, Hainaut P, Lowe AW, Beverloo BH, van Dekken H, Tilanus HW, Dinjens WN (2007) Mistaken Identity of Widely Used Esophageal Adenocarcinoma Cell Line TE-7. Cancer Res 67: 7996-8001. Brambilla C, Chabanon C, Diab S, Lorimier P, Delattre O, Godet J, Hainaut P, Houdet P, Fest T, Lazar W, Lidereau R, Maraninchi D (2006). Constitution Of A Prospective Tumor Cohort. Bull Cancer, 93: S229-36. Brem R, Cox DG, Chapot B, Moullan N, Romestaing P, Gerard JP, Pisani P, Hall J (2006) The XRCC1 -77T->C variant: haplotypes,

breast cancer risk, response to radiotherapy and the cellular response to DNA damage. Carcinogenesis 27: 2469-2474. Coste I, Freund JN, Spaderna S, Brabletz T, Renno T (2007) Precancerous lesions upon sporadic activation of beta-catenin in mice. Gastroenterology 132: 1299-1308. Dai M, Zhang WD, Clifford GM, Gheit T, He BC, Michael KM, Waterboer T, Hainaut P, Tommasino M, Franceschi S (2007) Human papillomavirus infection among 100 oesophageal cancer cases in the People’s Republic of China. Int J Cancer 121: 1396-1398. de Moraes E, Dar NA, Moura Gallo CV, Hainaut P (2007) Cross-talks between cyclooxygenase-2 and tumor suppressor protein p53: Balancing life and death during inflammatory stress and carcinogenesis. Int J Cancer 121: 929937. Galy O, Petit MA, Benjelloun S, Chevallier P, Chevallier M, Srivatanakul P, Karalak A, Carreira C, Lyandrat N, Essaid A, Trepo C, Hainaut P, Chemin I (2007). Efficient hepatitis C antigen immunohistological staining in sections of normal, cirrhotic and tumoral liver using a new monoclonal antibody directed against serum-derived HCV E2 glycoproteins. Cancer Lett 248: 81-88.

Molecular Carcinogenesis and Biology Group Gormally E, Caboux E, Vineis P, Hainaut P (2007). Circulating free DNA in plasma or serum as biomarker of carcinogenesis: practical aspects and biological significance. Mutat Res 635: 105-117. Gormally E, Vineis P, Matullo G, Veglia F, Caboux E, Le Roux E, Peluso M, Garte S, Guarrera S, Munnia A, Airoldi L, Autrup H, Malaveille C, Dunning A, Overvad K, Tjonneland A, Lund E, Clavel-Chapelon F, Boeing H, Trichopoulou A, Palli D, Krogh V, Tumino R, Panico S, Bueno-de-Mesquita HB, Peeters PH, Pera G, Martinez C, Dorronsoro M, Barricarte A, Navarro C, Quiros JR, Hallmans G, Day NE, Key TJ, Saracci R, Kaaks R, Riboli E, Hainaut P (2006) TP53 and KRAS2 mutations in plasma DNA of healthy subjects and subsequent cancer occurrence: a prospective study. Cancer Res 66: 6871-6876. Hainaut P (2006) Book review. Molecular Carcinogenesis and the Molecular Biology of Human Cancer. Int J Toxicology 25: 311-312. Hamimes S, Bourgeon D, Stasiak AZ, Stasiak A, Van Dyck E (2006) Nucleic acid-binding properties of the RRM-containing protein RDM1. Biochem Biophys Res Commun 344: 87-94. Herceg Z, Hainaut P (2007) Genetic and epigenetic alterations as biomarkers for cancer detection, diagnosis and prognosis. Mol Oncology 1: 26-41. Lambert R, Hainaut P (2007) Esophageal cancer: cases and causes (part I). Endoscopy 39: 550555. Lambert R, Hainaut P (2007) Esophageal cancer: the precursors (Part II). Endoscopy 39: 659664. Mathe E, Olivier M, Kato S, Ishioka C, Hainaut P, Tavtigian SV (2006). Computational approaches for predicting the biological effect of p53 missense mutations: a comparison of three sequence analysis based methods. Nucleic Acids Res 34: 1317-1325. Mathe E, Olivier M, Kato S, Ishioka C, Vaisman I, Hainaut P (2006) Predicting the transactivation activity of p53 missense mutants using a four-body potential score derived from Delaunay tessellations. Hum Mutat 27: 163-172. Matullo G, Dunning AM, Guarrera S, Baynes C, Polidoro S, Garte S, Autrup H, Malaveille C, Peluso M, Airoldi L, Veglia F, Gormally E, Hoek G, Krzyzanowski M, Overvad K, RaaschouNielsen O, Clavel-Chapelon F, Linseisen J, Boeing H, Trichopoulou A, Palli D, Krogh V, Tumino R, Panico S, Bueno-de-Mesquita HB, Peeters PH, Lund E, Pera G, Martinez C, Dorronsoro M, Barricarte A, Tormo MJ, Quiros JR, Day NE, Key TJ, Saracci R, Kaaks R, Riboli E, Vineis P (2006). DNA repair polymorphisms and cancer

risk in non-smokers in a cohort study. Carcinogenesis 27: 997-1007. Messaoudi L, Yang YG, Kinomura A, Stavreva DA, Yan G, Bortolin-Cavaillé ML, Arakawa H, Buerstedde JM, Hainaut P, Cavaillé J, Takata M, Van Dyck E (2007). Subcellular distribution of human RDM1 protein isoforms and their nucleolar accumulation in response to heat shock and proteotoxic stress. Nucleic Acids Res. 35(19):65716587. Mounawar M, Mukeria A, Le Calvez F, Hung RJ, Renard H, Cortot A, Bollart C, Zaridze D, Brennan P, Boffetta P, Brambilla E, Hainaut P (2007). Patterns of EGFR, HER2, TP53, and KRAS mutations of p14arf expression in nonsmall cell lung cancers in relation to smoking history. Cancer Res 67: 5667-5672. Olivier M, Langerod A, Carrieri P, Bergh J, Klaar S, Eyfjord J, Theillet C, Rodriguez C, Lidereau R, Bieche I, Varley J, Bignon Y, Uhrhammer N, Winqvist R, Jukkola-Vuorinen A, Niederacher D, Kato S, Ishioka C, Hainaut P, Borresen-Dale AL (2006). The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer. Clin Cancer Res 12: 1157-1167. Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P, Olivier M (2007). Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Hum Mutat 28: 622-629. Petitjean A, Achatz MI, Borresen-Dale AL, Hainaut P, Olivier M (2007) TP53 mutations in human cancers: functional selection and impact on cancer prognosis and outcomes. Oncogene 26: 2157-2165. Petitjean A, Hainaut P, Caron dF (2006). TP63 gene in stress response and carcinogenesis: a broader role than expected. Bull Cancer 93: E126E135. Roman S, Petre A, Thepot A, Hautefeuille A, Scoazec JY, Mion F, Hainaut P (2007). Downregulation of p63 upon exposure to bile salts and acid in normal and cancer esophageal cells in culture. Am J Physiol Gastrointest Liver Physiol 293: G45-G53. Treilleux I, Chapot B, Goddard S, Pisani P, Angele S, Hall J (2007). The molecular causes of low ATM protein expression in breast carcinoma; promoter methylation and levels of the catalytic subunit of DNA-dependent protein kinase. Histopathology 51: 63-69. Vaninetti NM, Geldenhuys L, Porter GA, Risch H, Hainaut P, Guernsey DL, Casson AG (2007) Inducible nitric oxide synthase, nitrotyrosine and p53 mutations in the molecular pathogenesis of Barrett’s esophagus and esophageal adenocarcinoma. Mol Carcinog, article available online.

van der Sande MA, Waight PA, Mendy M, Zaman S, Kaye S, Sam O, Kahn A, Jeffries D, Akum AA, Hall AJ, Bah E, McConkey SJ, Hainaut P, Whittle HC (2007) Long-term protection against HBV chronic carriage of Gambian adolescents vaccinated in infancy and immune response in HBV booster trial in adolescence. PLoS ONE 2: e753. Vineis P, Hoek G, Krzyzanowski M, VignaTaglianti F, Veglia F, Airoldi L, Autrup H, Dunning A, Garte S, Hainaut P, Malaveille C, Matullo G, Overvad K, Raaschou-Nielsen O, Clavel-Chapelon F, Linseisen J, Boeing H, Trichopoulou A, Palli D, Peluso M, Krogh V, Tumino R, Panico S, Bueno-de-Mesquita HB, Peeters PH, Lund EE, Gonzalez CA, Martinez C, Dorronsoro M, Barricarte A, Cirera L, Quiros JR, Berglund G, Forsberg B, Day NE, Key TJ, Saracci R, Kaaks R, Riboli E (2006). Air pollution and risk of lung cancer in a prospective study in Europe. Int J Cancer 119: 169-174. Vranic S, Kapur L, Foco F, Bilalovic N, Hainaut P (2006) The first case of Li-Fraumeni syndrome in Bosnia and Herzegovina: case report. Pathologica 98: 156-159 Book chapters Caboux E, Hainaut P, Gormally E (2007) Biological Resources Centers in Molecular Epidemiology Studies: Collecting, Storing and Analyzing Biospecimens. In Molecular Epidemiology of Chronic Diseases, in press, Vineis P, Garte S, Wild C (eds). Hainaut P. TP53: A master gene in normal and tumour suppression. In: Wright A and Hastie N. (Eds) Genes and Common Diseases: Genetics in Modern Medicine, Cambridge University Press, Cambridge, pp 233-244, 2007. Hainaut P, Vozar B, Rinaldi S, Caboux E. Chaper 7: The EPIC Biobank. In: Methods in Molecular Biology Book Series. Mounawar M, Hainaut P. Biologie cellulaire et moleculaire des cancer broncho-pulmonaires. In Cancers broncho-pulmonaires - Mise au point, Depierre A (ed) pp 145-160. John Libbey Eurotext Limited, Paris, 2006. Ohgaki H, Olivier M, Hainaut P (2007). LiFraumeni Syndrome and TP53 germline mutations. In World Health Organization Classification of Tumours of the Central Nervous System, Louis DN, Ohgaki H, Wiestler ODCWK (eds) pp 222-223. WHO Press: Lyon. Book Caboux E, Plymoth A, Hainaut P (eds). Common Minimum Technical Standards and Protocols for Biological Resource Centres Dedicated to Cancer Research, Working Group Report 2. IARC 2007. 53

Epigenetics Group (EGE) Group Head Dr Zdenko Herceg Group Secretary Mme Michelle Wrisez Visiting Scientists Dr Christelle Forcet (from May 2007) Ms Audrey Labalme (until August 2007)

Epigenetics represents a new frontier in cancer research owing to the fact that epigenetic changes have emerged as key mechanisms in cancer development. Epigenetics is the study of heritable modifications of DNA and associated proteins (histones) that are stably maintained during cell division. All critical changes in cancer cells, such as silencing of tumour suppressor genes, activation of oncogenes and defects in DNA repair, are caused not only by genetic but also by epigenetic mechanisms; therefore, understanding the epigenetic changes associated with cancer onset, progression and metastasis is fundamental in improving our abilities to successfully prevent, diagnose and treat cancer. Growing interest in the epigentics of cancer is further augmented by the recent realisation that epigenetic changes can be exploited as a powerful tool in the clinic and as a novel approach to early diagnosis, risk assessment and cancer prevention. However, although both scientific and medical communities now recognise the importance of epigenetic changes in cancer, the precise contribution of epigenetic mechanisms and gene targets of epigenetic alterations in human cancers are largely unknown. 54

Post-doctoral Fellows Dr Karen Balassiano (from November 2007) Dr Joanna Loizou (until January 2007) Dr Martin Finkbeiner (until December 2006) Dr Anupam Paliwal (from April 2007) Dr Héctor Hernandez Vargas (from May 2007)

Ms Sandra Fontanière (until August 2007) Mr Thomas Vaissière Miss Marie-Pierre Lambert ( January-March 2007 and from September 2007) Miss Maria Ouzounova ( January-March 2007 and from September 2007)

Students Mr Rabih Murr Miss Carla Sawan

Laboratory Technican Mr Cyrille Cuenin

Recognising the importance of the field of epigenetics, IARC has created the Epigenetics Group (EGE) which has initiated a new research programme in cancer epigenetics with the aims of investigating the contribution of epigenetic mechanisms to human cancer and assisting in the development of novel strategies for cancer risk assessment and prevention. Our programme also contributes to and benefits from the major axis of the Lyon Rhône-Alpes Cancéropôle. Our group founded the epigenetic network EpiPro (Epigenetic Profiling of Cancer), consisting of 15 regional research groups working on cancer epigenetics (supported by Institut National du Cancer, Cancéropôle, France). Epigenetic mechanisms in control of critical cellular processes and tumorigenesis Epigenetic information, encoded by both DNA methylation and histone modification patterns, is centrally connected to the control of normal cell proliferation and abnormal events that lead to oncogenic transformation; however, its underlying mechanisms remain unclear. While it is well established that aberrant epigenetic events can cause incorrect gene

activation and improper gene silencing, recent evidence argues that deregulated epigenetic states may contribute to cancer development by compromising other critical cellular processes such as DNA repair, DNA replication, cell cycle control and differentiation. Chromatin modifications and DNA methylation are two major epigenetic features whose disruption is a common hallmark of human cancer. Chromatin modifications occur at the level of histones — protein components of chromatin — that are targets for several post-translational covalent modifications, including acetylation, phosphorylation and methylation. This forms the "histone code" that extends and modulates the genetic (DNA) code. Factors that mediate chromatin modifying and remodelling activities include histone acetyltransferase (HATs), histone deacetylases (HDACs), histone methyltransferases (HMTs), histone demethylases, and adenosine triphosphate (ATP)-dependent nucleasome-remodelling factors. The biological function of chromatin modifying/remodelling activities in cellular processes and how chromatin modifications are disrupted in cancer are largely unknown.

Epigenetics Group

Acetylation of specific lysine residues within the amino-terminal tails of core histones is mediated by several HATs whose activity is dependent on the multiprotein HAT complexes. Recently, we have studied the role of HATs and histone acetylation in cellular functions using a loss-of-function approach in cells and mice combined with molecular/cellular and biochemical tools. We reported that abrogation of histone acetylation mediated by common HAT cofactor TRRAP revealed its essential function in embryonic development, cell cycle progression and mitotic control. To better understand the role of chromatinmodifying and remodelling activities in DNA repair, we have engineered a novel mammalian cellular system allowing examination of chromatin modification/remodelling and loading of DNA repair proteins specifically associated with chromatin surrounding DNA doublestrand breaks (DSBs). We found that the HAT cofactor TRRAP and Tip60 HAT bind to the chromatin surrounding sites of DSB in vivo, leading to histone hyperacetylation at DNA break sites. TRRAP depletion impairs both DNA damageinduced histone H4 hyper-acetylation and accumulation of repair molecules at sites of DSBs, resulting in defective homologous recombination (HR) repair despite the presence of a functional ATM-dependent DNA damage signalling cascade. These data thus reveal that cells may use the same basic mechanism involving TRRAPassociated HAT complexes to regulate distinct cellular processes, such as transcription and DNA repair. In a recent study, we discovered a novel mechanism for ubiquitination of β−Catenin, the central player in the canonical Wnt pathway that is frequently deregulated in human cancers. We found that this mechanism is independent of the cytoplasmic ubiquitination dependent on GSK- and CK1α-mediated phosporylation, and involves histone acetyltransfearse (HAT) cofactor TRRAP and Skp-Cullin-F-box (SCF) component Skp1, which mediate ubiquitination of β− Catenin in the context of the chromatin. Therefore, TRRAP/HAT participates in a novel mechanism of β-Catenin ubiquitination/destruction that acts after

nuclear localisation and transient activation of β-Catenin, and occurs on the chromatin ensuring shutdown of the Wnt signal. Our study thus provides evidence that there are two distinct regulatory mechanisms of β-Catenin stability and activity (cytoplasmic and chromatinbased) that functionally complement each other, and adds a new layer of regulation to the canonical Wnt pathway. Stem/progenitor cells in any given organism share an identical genome with other cell types; therefore it is obvious that their plasticity is due to epigenetic events. Importantly, cancer may originate from the transformation of normal stem/progenitor cells, therefore similar epigenetic mechanisms may regulate common features of stem cells and cancer stem cells. Deregulation of epigenetic states in cells with pluripotent potential may alter defining properties of stem cells, selfrenewal and differentiation potential, leading to cancer initiation and progression. Our genetic and cellular studies have shown that TRRAP/HAT is involved in a concerted and contextcoupled recruitment of HAT activity to chromatin, providing a functional link between specific chromatin modifications and cellular functions. Furthermore, we have found that TRRAP and TRRAPmediated histone acetylation may participate in the maintenance of stem cell identity through chromatin signature and this reconfiguration of chromatin. Detailed studies are in progress to elucidate changes in chromatin structure and function and possible changes in composition of key complexes as well as identity of the interacting proteins. Given that all cell types and many cancers are derived from pluripotent cells, a better understanding of epigenetic mechanisms controlling pluripotency and reprogramming will greatly affect many areas of modern biology and will help to tailor efficient therapeutic strategies. Study of DNA methylation changes in human cancers Various dietary and environmental factors are suspected to be implicated in the development of a wide range of human cancers by eliciting epigenetic changes; however, the contribution of epigenetic

mechanisms (such as DNA methylation and chromatin modifications) and the precise targets of epigenetic alterations during cancer development are largely unknown. Major obstacles in establishing a relationship between epigenetic changes and dietary and environmental factors in cancer is the fact that case–control studies tend to be too small and lack statistical power to identify the interactions between epigenetic changes and environmental and lifestyle factors. The EGE Group has initiated collaboration with Paolo Boffetta (GEC), Paul Brennan (GEP) and Pierre Hainaut (MCC) with the objective of assessing the contribution of epigenetic events induced by dietary and environmental factors to cancer development using large sample size. These studies take advantage of large case–control studies on lung and upperaero-digestive tract (UADT) cancers in Europe whose recruitment has been recently completed. This large sample size, together with quantitative measurement of changes in DNA methylation and chromatin modifications, ensures that epigenetic events with even moderate effects are positively identified, whereas false positive results are very limited. We have selected a number of genes involved in metabolism of carcinogens, DNA repair, cell cycle, and DNA methylation control, specifically RASSF1A, CDKN2A (p16), GSTP1, MGMT, p53, CDH1, MTHFR, TRRAP, MLH1, and BRCA1. We have established pyrosequencing assays for quantitative measurement of methylation at multiple CpG sites and have analyzed DNA methylation status in lung cancer samples and corresponding blood samples. The results obtained so far indicate that DNA methylation levels and patterns depend largely on the gene analysed, but also on the cancer type. For example, the methylation of GSTP1 promoter was completely absent in both lung cancer as well as blood samples of cases and controls. In contrast, the RASSF1 gene promoter was frequently methylated in lung cancer and head and neck cancer but not in blood samples, indicating that methylation of the RASSF1 gene promoter is a cancerspecific epigenetic event and could be a good epigenetic marker of tumorigenesis. In addition, we found that the CDKN2A 55

Molecular Carcinogenesis Cluster

role of epigenetic changes caused by established risk factors (e.g. tobacco smoking, diet, environmental and occupational exposures) as well as suspected risk factors in the diet and environment in specific human cancers, providing important information for the development of efficient strategies for risk assessment, molecular diagnostics and cancer prevention. The field of epigenetics has seen a surge of interest with the recent technical advances that allow robust, quantitative and genome-wide studies of epigenetic alterations, resulting in a flood of studies reporting epigenetic changes in human cancers. However, the data on epigenetic changes are heterogeneous and often range from the global measurement of a specific modification to the exact detection of epigenetic change or pattern. Furthermore, publication standards for data processing and presentation of epigenetic alterations have not yet been established. We have initiated the establishment of a cancer epigenetic database, prompted by the recognition by the scientific community of an urgent need to establish a systematic epigenetic database. The main aims of the epigenetic database at IARC will be: •

•

•

• promoter methylation was more frequent in lung than in UADT cancer, suggesting that CDKN2A promoter methylation may be cancer type-specific. Together, these results indicate that DNA methylation changes are cancerspecific and cancer-type-specific events,

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and that levels and patterns of DNA methylation in a limited panel of cancerassociated genes may be a good marker of tumorigenesis and provide significant diagnostic “coverage”. Results obtained, together with those of current and planned analyses, will allow the assessment of the

To provide the scientific community with a simple mechanism to access, retrieve and sort data on the prevalence and nature of epigenetic alterations in diverse forms of human cancers; To facilitate studies by comparing and analysing epigenetic changes with respect to cancer etiology and/or outcome; To help in establishing and promoting standards for the detection and reporting of epigenetic changes; and To provide a repository for data which by their nature are not systematically reported in primary publications. The database will provide systematic updates on the published literature on epigenetic changes in human cancer and may be exploited by IARC scientists as well as by the scientific community as a whole for pooled analyses.

Epigenetics Group

The EGE Group is grateful to the following for their collaboration in its projects: Bruno Amati, Milan, Italy; Laszlo Tora, Strasbourg, France; Zhao-Qi Wang, Jenna, Germany; Thomas Jenuwein, Vienna, Austria; Saadi Khochbin, Grenoble, France; Philippe Clezardin, Lyon, France; Claire Vourc’h, Grenoble, France; Eric Gilson, Lyon, France; Claude Sardet, Montpellier, France; Eric Julien, Montpellier, France; Stephan Dimitrov, Grenoble, France; Isabelle Chemin, Lyon, France; Jorg Tost, Paris, France; Jean-Pierre Issa, Houston, USA; Paolo Vineis, London, UK; Carlos Gonzalez, Barcelona, Spain; Vivek Shukla, Bethesda, USA; Ahmed Amine Khamlichi, Toulouse, France; Didier Trouche, Toulouse, France; Mark Billaud, Lyon, France; Alain Puisieux, Lyon, France; Caroline Moyret-Lalle, Lyon, France; Christelle Forcet, Lyon, France; Chantal Matar, Monton, Canada; Andreas Trumpp, Lausanne, Switzerland; Rafael Casellas, Bethesda, USA. Financial support from the following bodies is gratefully acknowledged: National Institutes of Health/National Cancer Institute (NIH/NCI), United States Association for International Cancer Research (AICR), United Kingdom Institut National du Cancer (Epigenetic profiling Network, EpiPro), France Association pour la Recherche sur le Cancer (ARC), France Ligue Nationale Contre le Cancer, France European Network of Excellence Environmental Cancer Risk, Nutrition and Individual Susceptibility (ECNIS) Ligue Nationale Contre le Cancer, Comité du Rhône, France European Molecular Biology Organisation (EMBO) Swiss Bridge Award

Publications Finkbeiner MG, Sawan C, Herceg Z (2007). A chromatin-based mechanism for b-Catenin ubiquitination and regulation of the canonical Wnt pathway. EMBO Rep. Under revision. Herceg Z, Hainaut P (2007) Genetic and epigenetic alterations as biomarkers for cancer detection, diagnosis and prognosis. Molecular Oncology, 1: 26–41. Herceg Z (2007). Epigenetics and cancer: towards an evaluation of the impact of environmental and dietary factors. Mutagenesis 22: 91-103. Loizou L, Murr R, Finkbeiner M, Sawan C, Wang ZQ, Herceg Z (2006). Epigenetic Infor-

mation in Chromatin: the Code of Entry for DNA Repair. Cell Cycle 5: 696-701.

break repair. Molecular Cellular Biology 26: 402412.

Murr R, Loizou L, Yang Y-G, Cuenin C, Li H, Wang ZQ, Herceg Z (2006). Histone acetylation by Trrap/Tip60 modulates loading of repair proteins and repair of DNA double strand breaks. Nature Cell Biology, 8: 91-99.

Shukla V, Vaissiere T, Herceg Z (2007). Histone acetylation and chromatin signature in stem cell identity and cancer. Mutat Res. [Aug 1 e-pub ahead of print].

Murr R, Vaissière T, Sawan C, Shukla V, Herceg Z (2007). Orchestration of chromatinbased processes: mind the TRRAP. Oncogene 13(26)37:5358-5372. Robert F, Hardy S, Nagy Z, Baldeyron C, Murr R, Déry U, Masson JY, Papadopoulo D, Herceg Z, Tora L (2006). The transcriptional HAT cofactor TRRAP associates with the MRN repair complex and plays a role in DNA double strand

Tardet M, Murr R, Herceg Z, Sardet C, Julien E. PR-Set7 dependent lysine methylation ensure genome replication and stability through S phase. Journal of Cell Biology, in press. Yang YG, Frappart P-O, Barrucand C, Dumon-Jones V, Michelon J, Herceg Z, Wang ZQ (2006). Nbs1 is required for the activation of both ATM and ATR kinases and modulates the choice of DNA double-strand break repair pathways. EMBO J 5: 5527-5538.

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Genetics and Epidemiology Cluster (GEC) Cluster Coordinator: Dr Paolo Boffetta

The overall goal of the Genetics and Epidemiology Cluster (GEC) of the International Agency for Research on Cancer is to elucidate the role of genetic factors in the human cancer burden, and their interactions with environmental factors, as a component of the Agency’s strategy of cancer control on a global scale. Three Research Groups are part of the Cluster, whose work extends from research on the structure and function of genetic alterations to the epidemiological investigation of the role of environment in human cancer. Research in the Cluster encompasses several disciplines, including molecular biology, molecular genetics, population genetics, genetic epidemiology, molecular epidemiology and classic epidemiology. The following criteria are used to prioritise research within the Cluster: (i) relevance of the research questions to the global burden of cancer, with particular emphasis on populations in low-resource countries, (ii) opportunity for methodological developments, with emphasis on interdisciplinary approaches, and (iii) opportunity for training and technology transfer. As a consequence, many of the projects are based on collaborations within the Cluster and with other Groups in the Agency, and

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essentially all projects consist international collaborations.

of

Genetic Cancer Susceptibility Group The Genetic Cancer Susceptibility Group is composed of two teams, the Genetic Services Platform Team, which is responsible for the laboratory component of medium- to large-scale genotyping studies conducted within the Cluster and by other Groups within the Agency, including standard sequencing and largescale resequencing projects, and the High-Risk Genes Team, which conducts research on known and strong candidate high-risk cancer susceptibility genes as well as studies directed towards discovery of new moderate-risk and high-risk susceptibility genes. Genetic Epidemiology Group The goals of the Genetic Epidemiology Group are to identify cancer predisposition genes and examine how these risks are modified by known environmental factors. These goals are achieved through large association studies with known polymorphisms and also through whole genome scans. Linkage analyses of highrisk families are also conducted. The current focus is on cancers related to tobacco and/or alcohol, including lung,

kidney and aero-digestive cancers, as well as cancers related to Epstein-Barr virus (EBV ) infection, including lymphomas and nasopharyngeal cancers. Lifestyle, Environment and Cancer Group In addition to working on the multicentre studies mentioned above, the Group on Lifestyle, Environment and Cancer coordinates international networks investigators aimed to exploit existing research resources (e.g. pooled analysis of gene-environment interactions). It also conducts prospective cohort studies in lowand medium-resource countries, to investigate the role of lifestyle and genetic factors in populations with specific cancer patterns. During 2006-2007, research within the Cluster has resulted in publication of 194 scientific papers; Cluster researchers have obtained grants from the European Commission and from several national programs, including notably the US National Cancer Institute, as well as from charities and foundations. The Cluster has hosted a large number of doctoral and post-doctoral students and visiting scientists.

Lifestyle, Environment and Cancer Group (GEE) Head Dr Paolo Boffetta Secretary Mrs Christine Bassier Ms V. Chabanis (until March 2007) Scientists Dr Eric Duell Dr Mia Hashibe Dr Mazda Jenab Dr Maria Leon Technical Assistants Mr Julien Berthiller Mrs Rim Boudjema Mr Gilles Ferro Mr Francois Deloche Mrs Véronique Luzon Visiting scientists Dr Barbara Charbotel (November 2005–March 2006) Prof. Harvey Checkoway ( June 2006–January 2007) Dr Naoko Kinugawa ( January 2007–July 2007)

Research in the Lifestyle and Environment Group (GEE) complements that conducted in the other groups of the cluster by aiming at identifying the environmental (in the broadest sense) causes of human cancer and their interactions with genetic factors. It also aims to contribute to the methodological development of the field of molecular and genetic epidemiology (Gillio-Tos 2007; Boffetta Carcinogenesis 2007], and of cancer prevention research, in particular in the field of tobacco control. The focus is on cancers of the lung, the upper aerodigestive tract, the pancreas and the kidney, and on lymphoma. The programme consists of multicentric international studies carried out in collaborating centres, in the

Dr Diana Menya (March 2006– April 2006) Dr Beate Ritz (August 2006– July 2007) Prof. Malcom Sim (from July 2007) Dr Oivind Skare (March 2007– April 2007) Dr Gajalakshmi Vendhan (November 2005–December 2006) Dr Jonathan Wakefield (September 2006–August 2007) Prof. Tongzhang Zheng (February 2007–May 2007 and June 2007–August 2007) Postdoctoral fellows Dr Silvia Balbo (from February 2006) Dr Sabiha Bouzbid (from November 2007) Dr Shu-Chun Chuang (from July 2007) Dr Elisabeth Couto (from March 2007) Dr Franck de Vocht ( June 2006 – May 2007) Dr Fabrizio Giannandrea (from April 2007)

coordination of networks of investigators, in the use of existing resources such as cancer registry data, and in the preparation of handbooks of tobacco control. Different types of study design are used (case– control, cohort, record linkage), and all field studies include a biological component. During 2006–2007 the group has completed a series of analyses of risk factors of cancers of the lung, the upper aerodigestive tract (including the oral cavity, pharynx, larynx and esophagus) and the kidney, and of lymphoma, based on large-scale case–control studies coordinated by GEE conducted in previous years in Europe and Latin America. Extensive genotyping of samples

Dr Julia Heck (from September 2006) Dr Farhad Islami (from June 2006) Dr Yuan-Chin Lee (from September 2006) Dr Amir Sapkota (until May 2007) Dr Janine Wichmann (from February 2007) Students Ms Shen-Chih Chang ( July 2007–September 2007) Mr Abdusamad Djonmuradov (April 2006–September 2006) Ms Géraldine Dominiak-Felden (May 2006–November 2006) Ms Mélanie Liegard (April 2006– November 2006) Ms Manuela Marron (from January 2005) Ms Mari Nelis ( June 2007– August 2007) Ms Ann Olsson (from January 2005) Ms Ghislaine Scelo (until December 2006)

collected in these studies has been conducted by the GCS and GEP groups. The full exploitation of this material will take several years; results reported during 2006–2007 include the effect of alcohol and tobacco on head and neck cancer in Central Europe (Hashibe IJC 2007; Hashibe AJE 2007), various occupational risk factors for lung cancer and head and neck cancer in Central Europe (Cassidy 2007; Zeka 2006; Carel 2006; Shanghina 2006; Durusoy 2006), and risk factors for lymphoma (Fortuny 2006; de Sanjose 2006; Besson 2006; Casey 2006; Nieters 2006). Results of analyses conducted in these studies on the effect of genetic variants on the risk of lung and head and neck cancer are reported in the section 59

Genetics and Epidemiology Cluster

concerning the GEP group. The analysis of environmental factors and their interactions with genetic variants, in particular for kidney cancer, will continue in 2008–2009. The work of the Group in the epidemiological studies described above has been extended to the coordination of international consortia, with the following goals:  Fast and coordinated replication of new findings,  Pooling of data for analysis for which large populations are needed, typically for gene-environment interactions, and  Setting standards for future epidemiological research. In particular, during 2006-2007 the Group played a key role in coordinating consortia of studies of lymphoma (InterLymph), in which pooled analyses have identified a role of selected genetic variants in immunological genes (Rothman 2006) and clarified the role of familial history of cancer (Wang 2007); of head and neck cancer (INHANCE), in which important results have been reported on the risk of tobacco smoking in non-drinkers and of alcohol drinking in non-smokers (Hashibe JNCI 2007); and, in collaboration with the GEP group, lung cancer (ILCCO). In addition, the group has played a key role in establishing consortia of investigators involved in molecular and genetic epidemiology of pancreatic cancer (PANC4) and squamous cell carcinoma of the esophagus (ESC3). 60

The group has also contributed to theoretical developments in the field of cancer consortia (Boffetta CEBP 2007; Seminara 2007; Ioannidis 2007). Finally, the group has been active in the establishment of the Asia Cohort Consortium, comprising ongoing and new prospective studies in Asia and the Pacific region. Another important area of work for the Group was its support to the establishment of prospective studies of cancer in populations in transition. In addition to the cohort study in the Russian Federation described in the GEP group section, a prospective study has been established in the Golestan province of Northeastern Iran, an area with very high incidence of esophageal cancer. Recruitment of inhabitants of the city of Gonbad and of rural areas of the province started in 2004 and will be completed in 2008, when the goal of 50 000 individuals, mainly of Turkmen ethnicity, will be reached. Each cohort member undergoes a detailed interview on dietary and lifestyle factors and provides samples of blood, urine, hair and nail. Follow-up began in 2006, and over 45 cases of esophageal cancer have been identified. Results of cross-sectional analyses on body mass and dietary factors have been reported (Barhami 2006; Malekshah 2006). Analyses of risk factors of esophageal cancer and other major outcomes will start in 2008. In addition, the feasibility of establishing a similar cohort in another area of Iran (Ardebil) will be explored. Preliminary work has

been carried out in Mumbai, Chennai and Trivandrum, India, to set up prospective cohorts of diet and cancer; the pilot studies will be completed in 2008. Work on large-scale cohorts in Sweden and Norway generated novel results on the use of cotinine as marker of tobacco smoking (Boffetta IJC 2006), the lack of association between serological markers of SV40 infection and mesothelioma risk (Kjaerheim 2007), the role of smokeless tobacco use in cancer of the pancreas and other organs (Luo 2007), and the role of tobacco smoking and body mass on risk of lymphoma, leukemia and melanoma (Odenbro 2007; Fernberg 2006; Fernberg 2007). The analysis of risk of cancer among individuals who underwent chromosomal aberration testing in six Central European countries has been completed (Boffetta AJE 2007; Norppa 2006); the pooled analysis of this cohort with previously established European cohorts will be completed in 2008. A further area of research has been the characterisation of the risk of second primaries in cancer patients. Based on a pooled dataset of over 4 000 000 cancer patients registered in 15 registries, analyses were conducted during 2006–2007 on the risk of second primaries after childhood leukemia and lymphoma (Maule 2007), testicular cancer (Richiardi IJC 2007), cancer of the fallopian tubes (Riska 2007), eye melanoma (Scelo IJC 2007), nasopharyngeal carcinoma (Scelo CCC 2007), pancreatic cancer (Shen 2006) and breast cancer (Mellemkjaer 2006). This project will be expanded to additional cancer registries and will include extended follow-up. The feasibility of collecting information on treatment will also be explored. In the field of occupational cancer, a case-control study of lung cancer was started among European asphalt workers, with the aim to clarify whether the increased risk detected in the historical cohort phase of the study is due to exposure to bitumen fumes, exposure to other agents in the asphalt industry, or to confounders such as tobacco smoking and exposures in other industries. The study will be completed in 2008. Additional results have been reported on risk of cancer among pulp and paper workers exposed to

Lifestyle, Environment and Cancer Group

chlorinated solvents (McLean 2006), and workers exposed to man-made vitreous fibres (Soldan 2006) and diesel engine exhaust (Richiardi 2006). The Group hosts two programmes on tobacco and alcohol research, which includes projects conducted by scientists in the Group as well as a coordinating component across other Groups and Clusters. With respect to tobacco prevention, the meeting of 17 international experts involved in the preparation of the latest IARC Handbook on Tobacco

Control, entitled Reversal of Risk After Quitting Smoking, took place in 2006 (Dresler 2006) and the book was published in 2007. A second meeting comprising 21 international experts was organised in March 2007, to prepare a Handbook on Methods for Evaluating Tobacco Control Policies. This Handbook is planned for publication in 2008. In 2008 another meeting will convene experts invited to produce a Handbook on Evaluation of Smoke-free Policies. Plans are underway for a subsequent Handbook, on evaluation

of fiscal policies, to be produced in 2009. With respect to alcohol, comprehensive reviews have been published on alcohol and cancer (Boffetta Lancet Oncol 2006; Boffetta IJC 2006), and a programme of systematic meta-analyses has been established. In addition, future work will include the biochemical analysis of samples of hard liquors from populations at high and low risk for alcohol-associated cancer.

The GEE Group is grateful to the following for their collaboration in its projects: Christian Abnet, Rockville, MD, USA; Hans-Olov Adami, Stockholm, Sweden; Antonio Agudo, Barcelona, Spain; Wolfgang Ahrens, Bremen, Germany; Jane Allen, Washington, USA; Aage Andersen, Olso, Norway; Nikolaus Becker, Heidelberg, Germany; Thomas Behrens, Bremen, Germany; Vladimir Bencko, Prague, Czech Republic; Simone Benhamou, Villejuif, France; Ingvar Bergdahl, Umea, Sweden; Jillian M. Birch, Manchester, UK; Aaron Blair, Rockville, MD, USA; Stefania Boccia, Rome, Italy; Christine Bouchardy, Geneva, Switzerland; Freddie Bray, Oslo, Norway; David Brewster, Edinburgh, GB; Elizabeth Brown, Rockville, MD, USA; Thomas Brüning, Bochum, Germany; Irene Brüske-Hohlfeld, Neuherberg, Germany; Patricia Buffler, Berkeley, CA, USA; Igor Burstyn, Edmonton, Canada; Cristina Canova, Padova, Italy; Neil Caporaso, Bethesda, USA; Adrian Cassidy, Liverpool, UK; Xavier Castellsague, Barcelona, Spain; Chu Chen, Seattle, USA; Wong-Ho Chow, Bethesda, MD, USA; Pier Luigi Cocco, Cagliari, Italy; Dario Consonni, Milan, Italy; David Christiani, Boston, USA; David Conway, Glasgow, GB; Giovanni Corrao, Milan, Italy; Dirk Dahmann, Bochum, Germany; Luigino Dal Maso, Aviano, Italy; Alexander Daudt, Porto Alegre, Brazil; Sandy Dawsey, Rockville, MD, USA; Carolyn Dresler, Little Rock, USA; José Eluf-Neto, São Paulo, Brazil; Eleonóra Fabiánová, Banská Bystrica, Slovakia; Leticia Fernandez, Havana, Cuba; John Field, Liverpool, UK; Leticia Fernandez, Havana, Cuba; Joelle Fevotte, Lyon, France; Tony Fletcher, London, UK; Lenka Foretova, Brno, Czech Republic; Christina Funch Lassen, Copenhagen, Denmark; Rainer van Gelder, Sankt Augustin, Germany; Maura Gillison, Baltimore, USA; Ellen Gritz, Houston, USA; Isabelle Groß, Bochum, Germany; Per Gustavsson, Stockholm, Sweden; Johnni Hansen, Copenhagen, Denmark; Joe Harford, Bethesda, MD, USA; Richard B. Hayes, Bethesda, USA; Dick Heederik, Utrecht, The Netherlands; Pirjo Heikkilä, Helsinki, Finland; Kari Hemminki, Huddinge, Sweden; Rolando Herrero, San José, Costa Rica; Ivana Holcatova, Prague, Czech Republic; Elisabeth Holly, San Francisco, USA; Mariette Hooiveld, Nijmegen, The Netherlands; Vladimir Janout, Olomouc, Czech Republic; Dhaval Jetly, Ahmedabad, India; Karl-Heinz Jöckel, Essen, Germany; Christoffer Johansen, Copenhagen, Denmark; Jøn G. Jønasson, Reykjavik, Iceland; Timo Kauppinen, Helsinki, Finland; Karl Kelsey, Boston, USA; Kristina Kjaerheim, Oslo, Norway; Sergio Koifman, Rio de Janeiro, Brazil; Pagona Lagiou, Athens, Greece; Maria Teresa Landi, Bethesda, USA; Jerome Lavoue, Lausanne, Switzerland; Hans Kromhout, Utrecht, The Netherlands; Pagona Lagiou, Athens, Greece; Sverre Langård, Oslo, Norway; Philip Lazarus, Hershey, USA; Fabio Levi, Lausanne, Switzerland; José Eduardo Levi, São Paulo, Brazil; Donghui Li, Houston, USA; Marja-Liisa Lindbohm, Helsinki, Finland; Jolanta Lissowska, Warsaw, Poland; Ray Lowry, Newcastle, UK; Danièle Luce, Villejuif, France; Gary Macfarlane, Manchester, UK; Manoj Mahimkar, Mumbai, India; Patrick Maisonneuve, Milan, Italy; Reza Malekzadeh, Tehran, Iran; Andrea ‘t Mannetje, Wellington, New Zealand; Dana Mates, Bucharest, Romania; Aleyamma Mathew, Trivandrum, India; Elena Matos, Buenos Aires, Argentina; Marc Maynadié, Dijon, France; Mary McBride, Vancouver, Canada; Bernard McCartan, Dublin, Ireland; Ana Menezes, Pelotas, Brazil; Sofia D. Merajver, Ann Arbor, MI, USA; Franco Merletti, Turin, Italy; Andres Metspalu, Tartu, Estonia; Dario Mirabelli, Turin, Italy; Anush Moukeria, Moscow, Russia; Joshua Muscat, Hershey, USA; Alexandra Nieters, Heidelberg, Germany; Hannu Norppa, Helsinki, Finland; Silvia Novello, Turin, Italy; Olof Nyrén, Stockholm, Sweden; Jørgen Olsen, Copenhagen, Denmark; Andrew Olshan, Chapel Hill, USA; Neil Pearce, Wellington, New Zealand; Beate Pesch, Bochum, Germany; Susan Peters, Utrecht, the Netherlands; Gloria Petersen, Rochester, USA; Richard Peto, Oxford, UK; Iris Pigeot, Bremen, Germany; Nils Plato, Stockholm, Sweden; Hermann Pohlabel, Bremen, Germany; Lützen Portengen, Utrecht,The Netherlands; Akram

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Genetics and Epidemiology Cluster

Pourshams, Tehran, Iran; Eero Pukkala, Helsinki, Finland; Mark Purdue, Bethesda, USA; Lorenzo Richiardi, Turin, Italy; Marjorie Romkes, Pittsburgh, USA; Peter Rudnai, Budapest, Hungary; Konrad Rydzynsky, Lodz, Poland; Suleeporn Sangrajrang, Bangkok, Thailand; Silvia de Sanjosé, Barcelona, Spain; Stephen Schwartz, Seattle, USA; Chia Kee Seng, Singapore; Jack Siemiatycki, Montreal, Canada; Judith Shaham, Raanana, Israel; K. T. Shenoy, Trivandrum, India; Lorenzo Simonato, Padova, Italy; Elaine Smith, Iowa city, USA; Amr Soliman, Ann Arbor, MI, USA; Masoud Sotoudeh, Tehran, Iran; Margaret Spitz, Taxes, USA; Anthony Staines, Dublin, Ireland; Eduardo De Stefani, Montevideo, Uruguay; Isabelle Stücker, Villejuif, France; Erich Sturgis, Houston, USA; Sunil Surange, Bhopal, India; Ole Svane, Copenhagen, Denmark; Neonila Szeszenia-Dabrowska, Lodz, Poland; Renato Talamini, Aviano, Italy; Jon M. Tonita, Saskatchewan, Canada; Elizabeth Tracey, Kings Cross, Australia; Antonia Trichopoulou, Athens, Greece; Dimitrios Trichopoulos, Athens, Greece; Donna Vallone, Washington, USA; Lars Vatten, Oslo, Norway; Carlo La Vecchia, Milan, Italy; Gajalakshmi Vendhan, Chennai, India; Roel Vermeulen, Utrecht, the Netherlands; Paolo Vineis, Turin, Italy; Frank de Vocht, Manchester, UK; Martine Vornanen, Tampere, Finland; Qingyi Wei, Houston, USA; Elisabete Weiderpass, Oslo, Norway; Denise Whitby, Frederick, MD, USA; Heinz-Erich Wichmann, Neuherberg, Germany; Debbie Winn, Bethesda, USA; Victor Wünsch-Filho, São Paulo, Brazil; David Zaridze, Moscow, Russia; Witold Zatonski, Warsaw, Poland; ZuoFeng Zhang, Los Angeles, USA; Ariana Znaor, Zagreb, Croatia. Financial support from the following bodies is gratefully acknowledged: European Commission US National Institutes of Health Agence Française de Sécurité Sanitaire de l’Environnement et du Travail (AFSSET), France Ligue Nationale contre le Cancer, Comité du Rhône, France Région Rhône-Alpes, France INSERM, France Brescia University, Italy HVBG, Hauptverband der gewerblichen Berufsgenossenschaften, Germany World Cancer Research Fund, UK Nutricia Research Foundation, the Netherlands Conservation of Clean Air and Water in Europe (Concawe) European Bitumen Association (Eurobitume) European Asphalt Paving Association (EAPA) National Asphalt Pavement Association (NAPA), USA Asphalt Roofing Manufacturers Association (ARMA) National Roofing Contractors Association (NRCA), USA

Publications Akbari MR, Malekzadeh R, Nasrollahzadeh D, Amanian D, Sun P, Islami F, Sotoudeh M, Semnani S, Boffetta P, Dawsey SM, Ghadirian P, Narod SA (2006). Familial risks of esophageal cancer among the Turkmen population of the Caspian littoral of Iran. Int J Cancer 119: 1047-1051. Bahrami H, Sadatsafavi M, Pourshams A, Kamangar F, Nouraie M, Semnani S, Brennan P, Boffetta P, Malekzadeh R (2006). Obesity and Hypertension in an Iranian Cohort Study; Iranian Women Experience Higher Rates of Obesity and Hypertension Than American Women. BMC Public Health 6: 158. Bamia C, Trichopoulos D, Ferrari P, Overvad K, Bjerregaard L, Tjonneland A, Halkjaer J, Clavel-Chapelon F, Kesse E, Boutron-Ruault

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MC, Boffetta P, Nagel G, Linseisen J, Boeing H, Hoffmann K, Kasapa C, Orfanou A, Travezea C, Slimani N, Norat T, Palli D, Pala V, Panico S, Tumino R, Sacerdote C, Bueno-deMesquita HB, Waijers PM, Peeters PH, van der Schouw YT, Berenguer A, Martinez-Garcia C, Navarro C, Barricarte A, Dorronsoro M, Berglund G, Wirfalt E, Johansson I, Johansson G, Bingham S, Khaw KT, Spencer EA, Key T, Riboli E, Trichopoulou A (2007). Dietary patterns and survival of older Europeans: The EPIC-Elderly Study (European Prospective Investigation into Cancer and Nutrition). Public Health Nutr 10: 590-598. Bardin-Mikolajczak A, Lissowska J, Zaridze D, Szeszenia-Dabrowska N, Rudnai P, Fabianova E, Mates D, Navratilova M, Bencko V, Janout V, Fevotte J, Fletcher T, t’Mannetje ‘,A., Brennan P, Boffetta P (2007). Occupation and

risk of lung cancer in Central and Eastern Europe: the IARC multi-center case-control study. Cancer Causes Control 18: 645-654. Becker N, de Sanjose S., Nieters A, Maynadie M, Foretova L, Cocco PL, Staines A, Alvaro T, Vornanen M, Brennan P, Boffetta P (2007). Birth order, allergies and lymphoma risk: Results of the European collaborative research project Epilymph. Leuk Res 31: 1365-1372. Besson H, Brennan P, Becker N, Nieters A, de Sanjose S., Font R, Maynadie M, Foretova L, Cocco PL, Staines A, Vornanen M, Boffetta P (2006). Tobacco smoking, alcohol drinking and non-Hodgkin’s lymphoma: A European multicenter case-control study (Epilymph). Int J Cancer 119: 901-908. Besson H, Brennan P, Becker N, de Sanjose S., Nieters A, Font R, Maynadie M, Foretova L,

Lifestyle, Environment and Cancer Group Cocco PL, Staines A, Vornanen M, Boffetta P (2006). Tobacco smoking, alcohol drinking and Hodgkin’s lymphoma: a European multicentre case-control study (EPILYMPH). Br J Cancer 95: 378-384. Besson H, Banks R, Boffetta P (2006). Cancer mortality among butchers: a 24-state death certificate study. J Occup Environ Med 48: 289293. Boffetta P (2007). Endotoxins in lung cancer prevention. J Natl Cancer Inst 99: 339. Boffetta P, Hashibe M, La Vecchia C, Zatonski W, Rehm J (2006). The burden of cancer attributable to alcohol drinking. Int J Cancer 119: 884-887. Boffetta P, Van der Hel O, Norppa H, Fabianova E, Fucic A, Gundy S, Lazutka J, Cebulska-Wasilewska A, Puskailerova D, Znaor A, Kelecsenyi Z, Kurtinaitis J, Rachtan J, Forni A, Vermeulen R, Bonassi S (2007). Chromosomal Aberrations and Cancer Risk: Results of a Cohort Study from Central Europe. Am J Epidemiol 165: 36-43. Boffetta P (2006). Human cancer from environmental pollutants: The epidemiological evidence. Mutat Res Rev Genet Toxicol 608: 157162. Boffetta P (2007). Epidemiology of peritoneal mesothelioma: a review. Ann Oncol 18: 985-990. Boffetta P (2007). [Transparency in the relationship between larc and the petroleum industry]. Epidemiol Prev 31: 170. Boffetta P (2007). Molecular cancer epidemiology: a tale of >3842 publications. Carcinogenesis 28: 1621. Boffetta P and de Vocht F (2007). Occupation and the risk of non-hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev 16: 369-372. Boffetta P, McLaughlin JK, La Vecchia C., Autier P, Boyle P (2007). ‘Environment’ in cancer causation and etiological fraction: limitations and ambiguities. Carcinogenesis 28: 913-915. Boffetta P, Armstrong B, Linet M, Kasten C, Cozen W, Hartge P (2007). Consortia in cancer epidemiology: lessons from InterLymph. Cancer Epidemiol Biomarkers Prev 16: 197-199. Boffetta P, Tarone RE, Blot WJ (2007). Survival in women after diagnosis of lung cancer. JAMA 297: 153. Boffetta P, Aagnes B., Weiderpass E, Andersen A (2006). Response to comments by Drs. Rutqvist, Lewin, Nilsson, Ramstrom, Rodu and Cole further to the publication of the manuscript “smokeless tobacco use and risk of

cancer of the pancreas and other organs”. Int J Cancer 118: 1586-1587. Boffetta P, Clark S, Shen M, Gislefoss R, Peto R, Andersen A (2006). Serum cotinine level as predictor of lung cancer risk. Cancer Epidemiol Biomarkers Prev 15: 1184-1188. Boffetta P, Hashibe M (2006). Alcohol and cancer. Lancet Oncol 7: 149-156. Boffetta P, Castaing M, Brennan P (2006). A Geographic Correlation Study of the Incidence of Pancreatic and other Cancers in Whites. Eur J Epidemiol 21: 39-46. Bosetti C, Boffetta P, La Vecchia C (2007). Occupational exposures to polycyclic aromatic hydrocarbons, and respiratory and urinary tract cancers: a quantitative review to 2005. Ann Oncol 18: 431-446. Brennan P, Crispo A, Zaridze D, SzeszeniaDabrowska N, Rudnai P, Lissowska J, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, Fletcher T, Boffetta P (2006). High Cumulative Risk of Lung Cancer Death among Smokers and Nonsmokers in Central and Eastern Europe. Am J Epidemiol 164: 1233-1241. Brennan P, McKay J, Moore L, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, Chow WH, Rothman N, Chabrier A, Gaborieau V, Odefrey F, Southey M, Hashibe M, Hall J, Boffetta P, Peto J, Peto R, Hung RJ (2007). Uncommon CHEK2 mis-sense variant and reduced risk of tobacco-related cancers: case control study. Hum Mol Genet 16: 1794-1801. Burstyn I, Kromhout H, Johansen C, Langard S, Kauppinen T, Shaham J, Ferro G, Boffetta P (2007). Bladder cancer incidence and exposure to polycyclic aromatic hydrocarbons among asphalt pavers. Occup Environ Med 64: 520-526. Campa D, Hashibe M, Zaridze D, SzeszeniaDabrowska N, Mates IN, Janout V, Holcatova I, Fabianova E, Gaborieau V, Hung RJ, Boffetta P, Brennan P, Canzian F (2007). Association of common polymorphisms in inflammatory genes with risk of developing cancers of the upper aerodigestive tract. Cancer Causes Control 18: 449-455. Carel R, Olsson AC, Zaridze D, SzeszeniaDabrowska N, Rudnai P, Lissowska J, Fabianova E, Cassidy A, Mates D, Bencko V, Foretova L, Janout V, Fevotte J, Fletcher T, t’Mannetje ‘,A., Brennan P, Boffetta P (2007). Occupational exposure to asbestos and manmade vitreous fibres and risk of lung cancer: a multicentre case-control study in Europe. Occup Environ Med 64: 502-508.

Casey R, Brennan P, Becker N, Boffetta P, Cocco P, Domingo-Domenech E, Foretova L, Nieters A, Sanjose SD, Staines A, Vornanen M, Maynadie M (2006). Influence of familial cancer history on lymphoid neoplasms risk validated in the large European case-control study epilymph. Eur J Cancer 42: 2570-2576. Cassidy A, t’Mannetje ‘,A., van Tongeren M., Field JK, Zaridze D, Szeszenia-Dabrowska N, Rudnai P, Lissowska J, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, Fevotte J, Fletcher T, Brennan P, Boffetta P (2007). Occupational exposure to crystalline silica and risk of lung cancer: a multicenter case-control study in Europe. Epidemiology 18: 36-43. Chao C, Zhang ZF, Berthiller J, Boffetta P, Hashibe M (2006). NAD(P)H:quinone oxidoreductase 1 (NQO1) Pro187Ser polymorphism and the risk of lung, bladder, and colorectal cancers: a meta-analysis. Cancer Epidemiol Biomarkers Prev 15: 979-987. Chuang SC, Hashibe M, Yu GP, Le AD, Cao W, Hurwitz EL, Rao JY, Neugut AI, Zhang ZF (2006). Radiotherapy for primary thyroid cancer as a risk factor for second primary cancers. Cancer Lett 238: 42-52. Chuang SC, Chen W, Hashibe M, Li G, Zhang ZF (2006). Survival rates of invasive breast cancer among ethnic Chinese women born in East Asia and the United States. Asian Pac J Cancer Prev 7: 221-226. de Sanjose S, Benavente Y, Nieters A, Foretova L, Maynadie M, Cocco PL, Staines A, Vornanen M, Boffetta P, Becker N, Alvaro T, Brennan P (2006). Association between Personal Use of Hair Dyes and Lymphoid Neoplasms in Europe. Am J Epidemiol 164: 4755. de Sanjosé S, Bosch R, Schouten T, Verkuijlen S, Nieters A, Foretova L, Maynadie M, Cocco PL, Staines A, Becker N, Brennan P, Benavente Y, Boffetta P, Meijer CJ, Middeldorp JM (2007). Epstein-Barr virus infection and risk of lymphoma: Immunoblot analysis of antibody responses against EBV-related proteins in a large series of lymphoma subjects and matched controls. Int J Cancer 121: 1806-1812. De Stefani E, Ronco AL, Boffetta P, DeoPellegrini H, Acosta G, Correa P, Mendilaharsu M (2006). Nutrient intake and risk of squamous cell carcinoma of the esophagus: a case-control study in Uruguay. Nutr Cancer 56: 149-157. De Stefani E, Boffetta P, Deo-Pellegrini H, Correa P, Ronco AL, Brennan P, Ferro G, Acosta G, Mendilaharsu M (2007). Nonalcoholic beverages and risk of bladder cancer in Uruguay. BMC cancer 7: 57.

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Genetics and Epidemiology Cluster De Stefani E, Boffetta P, Deneo-Pellegrini H, Ronco AL, Acosta G, Ferro G, Oreggia F, Leiva J (2007). The effect of smoking and drinking in oral and pharyngeal cancers: A case-control study in Uruguay. Cancer Lett 246: 282-289. De Stefani E, Boffetta P, Ronco AL, DeneoPellegrini H, Acosta G, Mendilaharsu M (2007). Dietary patterns and risk of laryngeal cancer: An exploratory factor analysis in Uruguayan men. Int J Cancer 121: 1086-1091. de Vocht F., Burstyn I, Straif K, Vermeulen R, Jakobsson K, Nichols L, Peplonska B, Taeger D, Kromhout H (2007). Occupational exposure to NDMA and NMor in the European rubber industry. J Environ Monit 9: 253-259. Dikshit RP, Ramadas K, Hashibe M, Thomas G, Somanathan T, Sankaranarayanan R (2006). Association between diabetes mellitus and premalignant oral diseases: A cross sectional study in Kerala, India. Int J Cancer 118: 453-457. Dikshit RP, Gillio-Tos A, Brennan P, De ML, Fiano V, Martinez-Penuela JM, Boffetta P, Merletti F (2007). Hypermethylation, risk factors, clinical characteristics, and survival in 235 patients with laryngeal and hypopharyngeal cancers. Cancer 110: 17451751. Durusoy R, Boffetta P, t’Mannetje ‘,A., Zaridze D, Zeszenia-Dabrowska N, Udnai P, Issowska J, Abianova E, Assidy A, Ates D, Encko V, Alajka F., Anout V, Evotte J, Letcher T, Rennan P (2006). Lung cancer risk and occupational exposure to meat and live animals. Int J Cancer 118: 2543-2547. Fernberg P, Odenbro A, Bellocco R, Boffetta P, Pawitan Y, Adami J (2006). Tobacco use, body mass index and the risk of malignant lymphomas—a nationwide cohort study in Sweden. Int J Cancer 118: 2298-2302. Fernberg P, Odenbro A, Bellocco R, Boffetta P, Pawitan Y, Zendehdel K, Adami J (2007). Tobacco use, body mass index, and the risk of leukemia and multiple myeloma: a nationwide cohort study in Sweden. Cancer Res 67: 59835986. Ferrari P, Jenab M, Norat T, Moskal A, Slimani N, Olsen A, Tjonneland A, Overvad K, Jensen MK, Boutron-Ruault MC, Clavel-Chapelon F, Morois S, Rohrmann S, Linseisen J, Boeing H, Bergmann M, Kontopoulou D, Trichopoulou A, Kassapa C, Masala G, Krogh V, Vineis P, Panico S, Tumino R, Gils CH, Peeters P, Bueno-de-Mesquita HB, Ocke MC, Skeie G, Lund E, Agudo A, Ardanaz E, Lopez DC, Sanchez MJ, Quiros JR, Amiano P, Berglund G, Manjer J, Palmqvist R, Guelpen BV, Allen N, Key T, Bingham S, Mazuir M, Boffetta P,

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Kaaks R, Riboli E (2007). Lifetime and baseline alcohol intake and risk of colon and rectal cancers in the European prospective investigation into cancer and nutrition (EPIC). Int J Cancer 121: 2065-2072. Figueiredo BC, Sandrini R, Zambetti GP, Pereira RM, Cheng C, Liu W, Lacerda L, Pianovski MA, Michalkiewicz E, Jenkins J, Rodriguez-Galindo C, Mastellaro MJ, Vianna S, Watanabe F, Sandrini F, Arram SI, Boffetta P, Ribeiro RC (2006). Penetrance of Adrenocortical Tumors Associated with the Germline TP53 R337H Mutation. J Med Genet 43: 91-96.

Gorin SS, Heck JE, Cheng B, Smith SJ (2006). Delays in breast cancer diagnosis and treatment by racial/ethnic group. Arch Intern Med 166: 2244-2252. Guha N, Boffetta P, Wunsch F, V, Eluf NJ, Shangina O, Zaridze D, Curado MP, Koifman S, Matos E, Menezes A, Szeszenia-Dabrowska N, Fernandez L, Mates D, Daudt AW, Lissowska J, Dikshit R, Brennan P (2007). Oral health and risk of squamous cell carcinoma of the head and neck and esophagus: results of two multicentric case-control studies. Am J Epidemiol 166: 1159-1173.

Fortuny J, de Sanjose S., Becker N, Maynadie M, Cocco PL, Staines A, Foretova L, Vornanen M, Brennan P, Nieters A, Alvaro T, Boffetta P (2006). Statin use and risk of lymphoid neoplasms: results from the European CaseControl Study EPILYMPH. Cancer Epidemiol Biomarkers Prev 15: 921-925.

Hall J, Hashibe M, Boffetta P, Gaborieau V, Moullan N, Chabrier A, Zaridze D, Shangina O, Szeszenia-Dabrowska N, Mates D, Janout V, Fabianova E, Holcatova I, Hung RJ, McKay J, Canzian F, Brennan P (2007). The association of sequence variants in DNA repair and cell cycle genes with cancers of the upper aerodigestive tract. Carcinogenesis 28: 665-671.

Fucic A, Znaor A, Strnad M, Van der Hel O, Aleksandrov A, Miskov S, Grah J, Sedlar M, Jazbec AM, Ceppi M, Vermeulen R, Boffetta P, Norppa H, Bonassi S (2007). Chromosome damage and cancer risk in the workplace: The example of cytogenetic surveillance in Croatia. Toxicol Lett 172: 4-11.

Hashibe M, Morgenstern H, Cui Y, Tashkin DP, Zhang ZF, Cozen W, Mack TM, Greenland S (2006). Marijuana use and the risk of lung and upper aerodigestive tract cancers: results of a population-based case-control study. Cancer Epidemiol Biomarkers Prev 15: 18291834.

Garcia Gomez M, Boffetta P, Caballero Klink JD, Espanol S, Gomez Quintana J. (2006). [Genitourinary diseases mortality in mercury miners]. Actas Urol Esp 30: 913-920.

Hashibe M, Boffetta P, Zaridze D, Shangina O, Szeszenia-Dabrowska N, Mates D, Janout V, Fabianova E, Bencko V, Moullan N, Chabrier A, Hung R, Hall J, Canzian F, Brennan P (2006). Evidence for an important role of alcohol- and aldehyde-metabolizing genes in cancers of the upper aerodigestive tract. Cancer Epidemiol Biomarkers Prev 15: 696-703.

Garcia Gomez M, Caballero Klink JD, Boffetta P, Espanol S, Sallsten G, Gomez QJ (2007). Exposure to mercury in the mine of Almaden. Occup Environ Med 64: 389-395. Garcia Gomez M, Boffetta P, Caballero Klink JD, Espanol S, Gomez Quintana J (2007). [Cardiovascular mortality in mercury miners.] In Spanish. Med Clin (Barc) 128: 766-771. Garcia Gomez M, Boffetta P, Caballero Klink JD, Espanol S, Gomez Quintana J, Colin D (2007). [Cancer mortality in mercury miners.] In Spanish. Gac Sanit 21: 210-217. Gemignani F, Landi S, Szeszenia-Dabrowska N, Zaridze D, Lissowska J, Rudnai P, Fabianova E, Mates D, Foretova L, Janout V, Bencko V, Gaborieau V, Gioia-Patricola L, Bellini I, Barale R, Canzian F, Hall J, Boffetta P, Hung RJ, Brennan P (2007). Development of lung cancer before the age of 50: the role of xenobiotic metabolizing genes. Carcinogenesis 28: 1287-1293. Gillio-Tos A, De Marco L, Fiano V, GarciaBragado F, Dikshit R, Boffetta P, Merletti F (2007). Efficient DNA extraction from 25year-old paraffin-embedded tissues: study of 365 samples. Pathology 39: 345-348.

Hashibe M, Boffetta P, Janout V, Zaridze D, Shangina O, Mates D, Szeszenia-Dabrowska N, Bencko V, Brennan P (2007). Esophageal cancer in Central and Eastern Europe: Tobacco and alcohol. Int J Cancer 120: 1518-1522. Hashibe M, Brennan P, Benhamou S, Castellsague X, Chen C, Curado MP, Dal Maso L., Daudt AW, Fabianova E, WunschFilho V, Franceschi S, Hayes RB, Herrero R, Koifman S, La Vecchia C, Lazarus P, Levi F, Mates D, Matos E, Menezes A, Muscat J, ElufNeto J, Olshan AF, Rudnai P, Schwartz SM, Smith E, Sturgis EM, Szeszenia-Dabrowska N, Talamini R, Wei Q, Winn DM, Zaridze D, Zatonski W, Zhang ZF, Berthiller J, Boffetta P (2007). Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. J Natl Cancer Inst 99: 777-789. Hashibe M, Boffetta P, Zaridze D, Shangina O, Szeszenia-Dabrowska N, Mates D, Fabianova

Lifestyle, Environment and Cancer Group E, Rudnai P, Brennan P (2007). Contribution of tobacco and alcohol to the high rates of squamous cell carcinoma of the supraglottis and glottis in Central Europe. Am J Epidemiol 165: 814-820. Hassan R, Alexander R, Antman K, Boffetta P, Churg A, Coit D, Hausner P, Kennedy R, Kindler H, Metintas M, Mutti L, Onda M, Pass H, Premkumar A, Roggli V, Sterman D, Sugarbaker P, Taub R, Verschraegen C (2006). Current treatment options and biology of peritoneal mesothelioma: meeting summary of the first NIH peritoneal mesothelioma conference. Ann Oncol 17: 1615-1619. Heck JE and Jacobson JS (2006). Asthma diagnosis among individuals in same-sex relationships. J Asthma 43: 579-584. Hayden PJ, Tewari P, Morris DW, Staines A, Crowley D, Nieters A, Becker N, De SS, Foretova L, Maynadie M, Cocco PL, Boffetta P, Brennan P, Chanock SJ, Browne PV, Lawler M (2007). Variation in DNA repair genes XRCC3, XRCC4, XRCC5 and susceptibility to myeloma. Hum Mol Genet 16: 3117-3127. Hsu CC, Chow WH, Boffetta P, Moore L, Zaridze D, Moukeria A, Janout V, Kollarova H, Bencko V, Navratilova M, SzeszeniaDabrowska N, Mates D, Brennan P (2007). Dietary risk factors for kidney cancer in eastern and central europe. Am J Epidemiol 166: 62-70. Hung RJ, Boffetta P, Canzian F, Moullan N, Szeszenia-Dabrowska N, Zaridze D, Lissowska J, Rudnai P, Fabianova E, Mates D, Foretova L, Janout V, Bencko V, Chabrier A, Landi S, Gemignani F, Hall J, Brennan P (2006). Sequence Variants in Cell Cycle Control Pathway, X-ray Exposure, and Lung Cancer Risk: A Multicenter Case-Control Study in Central Europe. Cancer Res 66: 8280-8286. Hung RJ, Moore L, Boffetta P, Feng BJ, Toro JR, Rothman N, Zaridze D, Navratilova M, Bencko V, Janout V, Kollarova H, SzeszeniaDabrowska N, Mates D, Chow WH, Brennan P (2007). Family history and the risk of kidney cancer: a multicenter case-control study in Central Europe. Cancer Epidemiol Biomarkers Prev 16: 1287-1290. Hung RJ, Hashibe M, McKay J, Gaborieau V, Szeszenia-Dabrowska N, Zaridze D, Lissowska J, Rudnai P, Fabianova E, Mates I, Foretova L, Janout V, Bencko V, Chabrier A, Moullan N, Canzian F, Hall J, Boffetta P, Brennan P (2007). Folate-related genes and the risk of tobaccorelated cancers in Central Europe. Carcinogenesis 28: 1334-1340. Ioannidis JPA, Gwinn M, Little J, Higgins JPT, Bernstein JL, Boffetta P, Bondy M, Bray MS, Brenchley PE, Buffler PA, Casas JP,

Chokkalingam A, Danesh J, Smith GD, Dolan S, Duncan R, Gruis NA, Hartge P, Hashibe M, Hunter DJ, Jarvelin MR, Malmer B, Maraganore DM, Newton-Bishop JA, O’Brien TR, Petersen G, Riboli E, Salanti G, Seminara D, Smeeth L, Taioli E, Timpson N, Uitterlinden AG, Vineis P, Wareham N, Winn DM, Zimmern R, Khoury MJ (2006). A road map for efficient and reliable human genome epidemiology. Nat Genet 38: 3-5. Kjaerheim K, Roe OD, Waterboer T, Sehr P, Rizk R, Dai HY, Sandeck H, Larsson E, Andersen A, Boffetta P, Pawlita M (2007). Absence of SV40 antibodies or DNA fragments in prediagnostic mesothelioma serum samples. Int J Cancer 120: 2459-2465. Kriebel D, Checkoway H, Pearce N (2007). Exposure and dose modelling in occupational epidemiology. Occup Environ Med 64: 492-498. Landi S, Gemignani F, Canzian F, Gaborieau V, Barale R, Landi D, Szeszenia-Dabrowska N, Zaridze D, Lissowska J, Rudnai P, Fabianova E, Mates D, Foretova L, Janout V, Bencko V, Gioia-Patricola L, Hall J, Boffetta P, Hung RJ, Brennan P (2006). DNA repair and cell cycle control genes and the risk of young-onset lung cancer. Cancer Res 66: 11062-11069. Linseisen J, Rohrmann S, Miller AB, Buenode-Mesquita HB, Buchner FL, Vineis P, Agudo A, Gram IT, Janson L, Krogh V, Overvad K, Rasmuson T, Schulz M, Pischon T, Kaaks R, Nieters A, Allen NE, Key TJ, Bingham S, Khaw KT, Amiano P, Barricarte A, Martinez C, Navarro C, Quiros R, Clavel-Chapelon F, Boutron-Ruault MC, Touvier M, Peeters PH, Berglund G, Hallmans G, Lund E, Palli D, Panico S, Tumino R, Tjonneland A, Olsen A, Trichopoulou A, Trichopoulos D, Autier P, Boffetta P, Slimani N, Riboli E (2007). Fruit and vegetable consumption and lung cancer risk: Updated information from the European Prospective Investigation into Cancer and Nutrition (EPIC). Int J Cancer 121: 1103-1114. Luo J, Ye W, Zendehdel K, Adami J, Adami HO, Boffetta P, Nyren O (2007). Oral use of Swedish moist snuff (snus) and risk for cancer of the mouth, lung, and pancreas in male construction workers: a retrospective cohort study. Lancet 369: 2015-2020. Malekshah AF, Kimiagar M, Saadatian-Elahi M, Pourshams A, Nouraie M, Goglani G, Hoshiarrad A, Sadatsafavi M, Golestan B, Yoonesi A, Rakhshani N, Fahimi S, Nasrollahzadeh D, Salahi R, Ghafarpour A, Semnani S, Steghens JP, Abnet CC, Kamangar F, Dawsey SM, Brennan P, Boffetta P, Malekzadeh R (2006). Validity and reliability of a new food frequency questionnaire compared to 24 h recalls and biochemical

measurements: pilot phase of Golestan cohort study of esophageal cancer. Eur J Clin Nutr 60: 971-977. Marques CF, Koifman S, Koifman RJ, Boffetta P, Brennan P, Hatagima A (2006). Influence of CYP1A1, CYP2E1, GSTM3 and NAT2 genetic polymorphisms in oral cancer susceptibility: results from a case-control study in Rio de Janeiro. Oral Oncol 42: 632-637. Maule M, Scelo G, Pastore G, Brennan P, Hemminki K, Tracey E, Sankila R, Weiderpass E, Olsen JH, McBride ML, Brewster DH, Pompe-Kirn V, Kliewer EV, Chia KS, Tonita JM, Martos C, Jonasson JG, Merletti F, Boffetta P (2007). Risk of second malignant neoplasms after childhood leukemia and lymphoma: an international study. J Natl Cancer Inst 99: 790-800. McClean MD, Rinehart RD, Sapkota A, Cavallari JM, Herrick RF (2007). Dermal exposure and urinary 1-hydroxypyrene among asphalt roofing workers. J Occup Environ Hyg 4 Suppl 1: 118-126. McLean D, Pearce N, Langseth H, Jappinen P, Szadkowska-Stanczyk I, Persson B, Wild P, Kishi R, Lynge E, Henneberger P, Sala M, Teschke K, Kauppinen T, Colin D, Kogevinas M, Boffetta P (2006). Cancer mortality in workers exposed to organochlorine compounds in the pulp and paper industry: an international collaborative study. Environ Health Perspect 114: 1007-1012. Mellemkjaer L, Friis S, Olsen JH, Scelo G, Hemminki K, Tracey E, Andersen A, Brewster DH, Pukkala E, McBride ML, Kliewer EV, Tonita JM, Kee-Seng C, Pompe-Kirn V, Martos C, Jonasson JG, Boffetta P, Brennan P (2006). Risk of second cancer among women with breast cancer. Int J Cancer 118: 2285-2292. Moore LE, Brennan P, Karami S, Hung RJ, Hsu C, Boffetta P, Toro J, Zaridze D, Janout V, Bencko V, Navratilova M, SzeszeniaDabrowska N, Mates D, Mukeria A, Holcatova I, Welch R, Chanock S, Rothman N, Chow WH (2007). Glutathione S-transferase polymorphisms, cruciferous vegetable intake and cancer risk in the Central and Eastern European Kidney Cancer Study. Carcinogenesis 28: 1960-1964. Moore T, Brennan P, Becker N, de Sanjose S., Maynadie M, Foretova L, Cocco P, Staines A, Nieters A, Font R, t Mannetje A, haim-Luzon V, Boffetta P (2007). Occupational exposure to meat and risk of lymphoma: A multicenter case-control study from Europe. Int J Cancer 121: 2761-2766. Mounawar M, Mukeria A, Le Calvez F, Hung RJ, Renard H, Cortot A, Bollart C, Zaridze D,

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Genetics and Epidemiology Cluster Brennan P, Boffetta P, Brambilla E, Hainaut P (2007). Patterns of EGFR, HER2, TP53, and KRAS mutations of p14arf expression in nonsmall cell lung cancers in relation to smoking history. Cancer Res 67: 5667-5672. Nieters A, Kallinowski B, Brennan P, Ott M, Maynadie M, Benavente Y, Foretova L, Cocco PL, Staines A, Vornanen M, Whitby D, Boffetta P, Becker N, De SS (2006). Hepatitis C and Risk of Lymphoma: Results of the European Multicenter Case-Control Study EPILYMPH. Gastroenterology 131: 1879-1886. Norppa H, Bonassi S, Hansteen IL, Hagmar L, Stromberg U, Rossner P, Boffetta P, Lindholm C, Gundy S, Lazutka J, Cebulska-Wasilewska A, Fabianova E, Sram RJ, Knudsen LE, Barale R, Fucic A (2006). Chromosomal aberrations and SCEs as biomarkers of cancer risk. Mutat Res Fund Mol Mechan Mutagen 600: 37-45. Odenbro A, Gillgren P, Bellocco R, Boffetta P, Hakansson N, Adami J (2007). The risk for cutaneous malignant melanoma, melanoma in situ and intraocular malignant melanoma in relation to tobacco use and body mass index. Br J Dermatol 156: 99-105. Parent ME, Rousseau MC, Boffetta P, Cohen A, Siemiatycki J (2007). Exposure to diesel and gasoline engine emissions and the risk of lung cancer. Am J Epidemiol 165: 53-62. Pearce N, Checkoway H, Kriebel D (2007). Bias in occupational epidemiology studies. Occup Environ Med 64: 562-568. Pianovski MA, Maluf EM, de Carvalho DS, Ribeiro RC, Rodriguez-Galindo C, Boffetta P, Zancanella P, Figueiredo BC (2006). Mortality rate of adrenocortical tumors in children under 15 years of age in Curitiba, Brazil. Pediatr Blood Cancer 47: 56-60. Puente D, Hartge P, Greiser E, Cantor KP, King WD, Gonzalez CA, Cordier S, Vineis P, Lynge E, Chang-Claude J, Porru S, Tzonou A, Jockel KH, Serra C, Hours M, Lynch CF, Ranft U, Wahrendorf J, Silverman D, Fernandez F, Boffetta P, Kogevinas M (2006). A pooled analysis of bladder cancer case-control studies evaluating smoking in men and women. Cancer Causes Control 17: 71-79. Raimondi S, Paracchini V, Autrup H, BarrosDios JM, Benhamou S, Boffetta P, Cote ML, Dialyna IA, Dolzan V, Filiberti R, Garte S, Hirvonen A, Husgafvel-Pursiainen K, Imyanitov EN, Kalina I, Kang D, Kiyohara C, Kohno T, Kremers P, Lan Q, London S, Povey AC, Rannug A, Reszka E, Risch A, Romkes M, Schneider J, Seow A, Shields PG, Sobti RC, Sorensen M, Spinola M, Spitz MR, Strange RC, Stucker I, Sugimura H, To-Figueras J, Tokudome S, Yang P, Yuan JM, Warholm M,

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Taioli E (2006). Meta- and Pooled Analysis of GSTT1 and Lung Cancer: A Huge-GSEC Review. Am J Epidemiol 164: 1027-1042.

Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). Am J Epidemiol 164: 1103-1114.

Rehm J, Sulkowska U, Manczuk M, Boffetta P, Powles J, Popova S, Zatonski W (2007). Alcohol accounts for a high proportion of premature mortality in central and eastern Europe. Int J Epidemiol 36: 458-467.

Rohrmann S, Becker N, Linseisen J, Nieters A, Rudiger T, Raaschou-Nielsen O, Tjonneland A, Johnsen HE, Overvad K, Kaaks R, Bergmann MM, Boeing H, Benetou V, Psaltopoulou T, Trichopoulou A, Masala G, Mattiello A, Krogh V, Tumino R, Gils CH, Peeters PH, Bueno-deMesquita HB, Ros MM, Lund E, Ardanaz E, Chirlaque MD, Jakszyn P, Larranaga N, Losada A, Martinez-Garcia C, Agren A, Hallmans G, Berglund G, Manjer J, Allen NE, Key TJ, Bingham S, Khaw KT, Slimani N, Ferrari P, Boffetta P, Norat T, Vineis P, Riboli E (2007). Fruit and vegetable consumption and lymphoma risk in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cancer Causes Control 18: 537-549.

Richiardi L, Mirabelli D, Calisti R, Ottino A, Ferrando A, Boffetta P, Merletti F (2006). Occupational exposure to diesel exhausts and risk for lung cancer in a population-based casecontrol study in Italy. Ann Oncol 17: 1842-1847. Richiardi L, Scelo G, Boffetta P, Hemminki K, Pukkala E, Olsen JH, Weiderpass E, Tracey E, Brewster DH, McBride ML, Kliewer EV, Tonita JM, Pompe-Kirn V, Kee-Seng C, Jonasson JG, Martos C, Brennan P (2007). Second malignancies among survivors of germcell testicular cancer: a pooled analysis between 13 cancer registries. Int J Cancer 120: 623-631. Rinaldi S, Dossus L, Lukanova A, Peeters PH, Allen NE, Key T, Bingham S, Khaw KT, Trichopoulos D, Trichopoulou A, Oikonomou E, Pera G, Larranaga N, Martinez-Garcia C, Ardanaz E, Quiros JR, Tormo MJ, Tjonneland A, Olsen A, Overvad K, Chang-Claude J, Linseisen J, Schulz M, Boeing H, Van Gils CH, Bueno-de-Mesquita BH, Pala V, Palli D, Panico S, Tumino R, Vineis P, Clavel-Chapelon F, Mesrine S, Boutron-Ruault MC, Lundin E, Agren A, Berglund G, Manjer J, Kumle M, Lund E, Slimani N, Saracci R, Riboli E, Kaaks R (2007). Endogenous androgens and risk of epithelial ovarian cancer: results from the European Prospective Investigation into Cancer and Nutrition (EPIC). Cancer Epidemiol Biomarkers Prev 16: 23-29. Riska A, Pukkala E, Scelo G, Mellemkjaer L, Hemminki K, Weiderpass E, McBride ML, Pompe-Kirn V, Tracey E, Brewster DH, Kliewer EV, Tonita JM, Kee-Seng C, Jonasson JG, Martos C, Boffetta P, Brennan P (2007). Second primary malignancies in females with primary fallopian tube cancer. Int J Cancer 120: 2047-2051. Rohrmann S, Linseisen J, Boshuizen HC, Whittaker J, Agudo A, Vineis P, Boffetta P, Jensen MK, Olsen A, Overvad K, Tjonneland A, Boutron-Ruault MC, Clavel-Chapelon F, Bergmann MM, Boeing H, Allen N, Key T, Bingham S, Khaw KT, Kyriazi G, Soukara S, Trichopoulou A, Panico S, Palli D, Sieri S, Tumino R, Peeters PH, Bueno-de-Mesquita HB, Buchner FL, Gram IT, Lund E, Ardanaz E, Chirlaque MD, Dorronsoro M, Perez MJ, Quiros JR, Berglund G, Janzon L, Rasmuson T, Weinehall L, Ferrari P, Jenab M, Norat T, Riboli E (2006). Ethanol Intake and Risk of Lung

Ronco AL, De Stefani E, Boffetta P, DeneoPellegrini H, Acosta G, Mendilaharsu M (2006). Food patterns and risk of breast cancer: A factor analysis study in Uruguay. Int J Cancer 119: 1672-1678. Rothman N, Skibola CF, Wang SS, Morgan G, Lan Q, Smith MT, Spinelli JJ, Willett E, de Sanjose S., Cocco P, Berndt SI, Brennan P, Brooks-Wilson A, Wacholder S, Becker N, Hartge P, Zheng T, Roman E, Holly EA, Boffetta P, Armstrong B, Cozen W, Linet M, Bosch FX, Ennas MG, Holford TR, Gallagher RP, Rollinson S, Bracci PM, Cerhan JR, Whitby D, Moore PS, Leaderer B, Lai A, Spink C, Davis S, Bosch R, Scarpa A, Zhang Y, Severson RK, Yeager M, Chanock S, Nieters A (2006). Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph Consortium. Lancet Oncol 7: 27-38. Sandeep TC, Strachan MW, Reynolds RM, Brewster DH, Scelo G, Pukkala E, Hemminki K, Anderson A, Tracey E, Friis S, McBride ML, Kee-Seng C, Pompe-Kirn V, Kliewer EV, Tonita JM, Jonasson JG, Martos C, Boffetta P, Brennan P (2006). Second primary cancers in thyroid cancer patients: a multinational record linkage study. J Clin Endocrinol Metab 91: 18191825. Sangrajrang S, Schmezer P, Burkholder I, Boffetta P, Brennan P, Woelfelschneider A, Bartsch H, Wiangnon S, Cheisilpa A, Popanda O (2007). The XRCC3 Thr241Met polymorphism and breast cancer risk: a casecontrol study in a Thai population. Biomarkers 12: 523-532. Sapkota A, Halden RU, Dominici F, Groopman JD, Buckley TJ (2006). Urinary biomarkers of 1,3-butadiene in environmental settings using liquid chromatography isotope

Lifestyle, Environment and Cancer Group dilution tandem mass spectrometry. Chem Biol Interact 160: 70-79. Sapkota A, Gajalakshmi V, Jetly DH, Roychowdhury S, Dikshit RP, Brennan P, Hashibe M, Boffetta P (2007). Smokeless tobacco and increased risk of hypopharyngeal and laryngeal cancers: A multicentric casecontrol study from India. Int J Cancer 121: 1793-1798. Sartor SG, Eluf-Neto J, Travier N, WunschFilho V, Arcuri AS, Kowalski LP, Boffetta P (2007). [Occupational risks for laryngeal cancer: a case-control study.] [In Portugese]. Cad Saude Publica 23: 1473-1481. Scélo G, Boffetta P, Hemminki K, Pukkala E, Olsen JH, Andersen A, Tracey E, Brewster DH, McBride M, Kliewer EV, Tonita JM, PompeKirn V, Chia KS, Jonasson JG, Martos C, Colin D, Brennan P (2006). Associations between small intestine cancer and other primary cancers: an international population-based study. Int J Cancer 118: 189-196. Scelo G, Boffetta P, Autier P, Hemminki K, Pukkala E, Olsen JH, Weiderpass E, Tracey E, Brewster DH, McBride ML, Kliewer EV, Tonita JM, Pompe-Kirn V, Chia KS, Jonasson JG, Martos C, Giblin M, Brennan P (2007). Associations between ocular melanoma and other primary cancers: An international population-based study. Int J Cancer 120: 152159. Scelo G, Boffetta P, Corbex M, Chia KS, Hemminki K, Friis S, Pukkala E, Weiderpass E, McBride ML, Tracey E, Brewster DH, Pompe-Kirn V, Kliewer EV, Tonita JM, Martos C, Jonasson JG, Brennan P (2007). Second primary cancers in patients with

nasopharyngeal carcinoma: a pooled analysis of 13 cancer registries. Cancer Causes Control 18: 269-278.

fibre burden in lung cancer cases employed in the rock and slag wool industry. Ann Occup Hyg 50: 241-248.

Seminara D, Khoury MJ, O’Brien TR, Manolio T, Gwinn ML, Little J, Higgins JP, Bernstein JL, Boffetta P, Bondy M, Bray MS, Brenchley PE, Buffler PA, Casas JP, Chokkalingam AP, Danesh J, Davey SG, Dolan S, Duncan R, Gruis NA, Hashibe M, Hunter D, Jarvelin MR, Malmer B, Maraganore DM, Newton-Bishop JA, Riboli E, Salanti G, Taioli E, Timpson N, Uitterlinden AG, Vineis P, Wareham N, Winn DM, Zimmern R, Ioannidis JP (2007). The emergence of networks in human genome epidemiology: challenges and opportunities. Epidemiology 18: 1-8.

Tuohimaa P, Pukkala E, Scelo G, Olsen JH, Brewster DH, Hemminki K, Tracey E, Weiderpass E, Kliewer EV, Pompe-Kirn V, McBride ML, Martos C, Chia KS, Tonita JM, Jonasson JG, Boffetta P, Brennan P (2007). Does solar exposure, as indicated by the nonmelanoma skin cancers, protect from solid cancers: Vitamin D as a possible explanation. Eur J Cancer 43: 1701-1712.

Shangina O, Brennan P, Szeszenia-Dabrowska N, Mates D, Fabianova E, Fletcher T, t’Mannetje ‘,A., Boffetta P, Zaridze D (2006). Occupational exposure and laryngeal and hypopharyngeal cancer risk in central and eastern Europe. Am J Epidemiol 164: 367-375. Shen M, Boffetta P, Olsen JH, Andersen A, Hemminki K, Pukkala E, Tracey E, Brewster DH, McBride ML, Pompe-Kirn V, Kliewer EV, Tonita JM, Chia KS, Martos C, Jonasson JG, Colin D, Scélo G, Brennan P (2006). A pooled analysis of second primary pancreatic cancer. Am J Epidemiol 163: 502-511. Sjodahl K, Jansson C, Bergdahl IA, Adami J, Boffetta P, Lagergren J (2007). Airborne exposures and risk of gastric cancer: A prospective cohort study. Int J Cancer 120: 2013-2018.

Wang SS, Slager SL, Brennan P, Holly EA, de Sanjose S., Bernstein L, Boffetta P, Cerhan JR, Maynadie M, Spinelli JJ, Chiu BC, Cocco P, Mensah F, Zhang Y, Nieters A, Dal Maso L., Bracci PM, Costantini AS, Vineis P, Severson RK, Roman E, Cozen W, Weisenburger D, Davis S, Franceschi S, La Vecchia C., Foretova L, Becker N, Staines A, Vornanen M, Zheng T, Hartge P (2007). Family history of hematopoietic malignancies and risk of nonHodgkin lymphoma (NHL): a pooled analysis of 10,211 cases and 11,905 controls from the International Lymphoma Epidemiology Consortium (InterLymph). Blood 108: 34793488. Zeka A, t’Mannetje ‘,A., Zaridze D, SzeszeniaDabrowska N, Rudnai P, Lissowska J, Fabianova E, Mates D, Bencko V, Navratilova M, Cassidy A, Janout V, Travier N, Fevotte J, Fletcher T, Brennan P, Boffetta P (2006). Lung Cancer and Occupation in Nonsmokers: A Multicenter Case-Control Study in Europe. Epidemiology 17: 615-623.

Soldan K, Pooley FD, Hansen J, Andersen A, Chang-Claude J, Ferro G, Ohgaki H, Skov BG, Cherrie JW, Saracci R, Boffetta P (2006). Lung

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Genetic Epidemiology Group (GEP)

Group Head Dr Paul Brennan

Ms Amelie Chabrier Ms Colette Bonnardel (until May 2007) Ms Stéphanie Monnier (until November 2007)

Secretary Ms Yvette Granjard Scientists Dr James McKay Dr M. Corbex (until January 2006)

Visiting scientists Dr Rayjean Hung (until November 2007) Dr Majida Jalbout (until September 2006) Dr Olga Sinilnikova (until July 2007) Dr Bingjian Feng (until August 2006)

Technical Assistants Mrs Valérie Gaborieau Ms Hélène Renard

It has long been recognised that family members of an individual with cancer are themselves at increased risk of cancer. This familial clustering may stem from inherited defects in specific genes, from shared environmental exposures among family members or from interaction between specific genetic and environmental factors. By identifying genetic variants that increase the risk of common cancers, and how these genetic effects interact with known environmental risk factors, it will be possible to elucidate the reasons why cancers develop and to potentially identify individuals who are at a particularly high risk. The goals of the Genetic Epidemiology (GEP) Group are to: • Conduct large case–control studies of specific cancers and participate in international consortia in order to ensure that studies have adequate sample size. • Identify cancer-predisposition genes through linkage analysis of high-risk families, through association or case– control studies with known polymorphisms and, in the future, through whole genome scans. 68

•

•

Estimate the age- and site-specific risks of cancer conferred by mutations and/or polymorphic variations in these genes, and examine how these risks are modified by known environmental factors. Contribute to the development of statistical tools for analysing genetic data.

Alcohol- and tobacco-related cancers While it is clear that lung and upper aerodigestive tract cancers are caused predominantly by exposure to tobacco and alcohol products, only a minority of heavy smokers and heavy drinkers develop such a cancer. Furthermore, second primary cancers in this group are common, suggesting a high initial genetic susceptibility among these individuals. However, the nature of the genetic variation is not clear. We have completed genetic analysis of 120 variants in a variety of potential susceptibility genes among 2000 lung cancer cases, 1000 head and neck cancer cases and 3000 controls in the Central European population. Variants in three genes, CHEK2, ADH1B and ADH7, are particularly noteworthy and have been

Dr Katarzyna Szymanska (from October 2005) Dr Karina Braga Ribeiro (from October 2007) Students Ms Meili Baragatti (April 2006October 2006) Mr Yi Ren Wang ( July 2007September 2007) Mrs Jin Hee Kim ( JulySeptember 2007) Mr Vijay Vel Jayaprakash

replicated independently. In CHEK2, we found a strong inverse association with the minor allele of I157T (rs17879961) and lung cancer (RR=0.44, 95% CI 0.31–0.63) that was strongest in squamous cell carcinoma (RR=0.20, 95% CI 0.10–0.38). A similar inverse association was noted in upper aerodigestive cancer, with carriers having a RR=0.44 (95% CI 0.26–0.73). This was contrary to our expectations as this same variant has been found to be associated with an increase in risk of other forms of cancer such as breast, prostate and kidney cancer. This strong inverse association between the I157T variant and lung cancer was replicated in an independent study of 716 lung cancer patients and over 5496 controls from Poland (OR=0.34, 95%CI 0.20–0.58) (Cybulski, personal communication). In the alcohol dehydrogenase (ADH) gene cluster, one missense variant in ADH1B (rs1229984 R48H) and one missense variant in ADH7 (rs1573496 G92A) were found to be associated with a decreased risk of upper aerodigestive cancers in the Central European, Latin American and Western European upper aerodigestive cancer studies. Both variants appeared independent of one another, and

Genetics Epidemiology Group

conferred RRs of 0.54 (95% CI 0.46–0.65, p=10-11) and 0.68 (95% CI 0.60–0.77, p=10-9), using a combined series of 4014 cases and 5290 controls from all three upper aerodigestive cancer studies. Genetic variation in CHEK2, ADH1B and ADH7 appears to play a role in susceptibility to lung and upper aerodigestive cancers, however, they clearly do not account for all the genetic susceptibility to lung and upper aerodigestive cancers. Multiphased genome-wide association studies are currently underway in collaboration with the Centre National de Génotypage (France) to help identify new genes for lung, kidney and aerodigestive cancers. The Group is also coordinating the International Lung Cancer Consortium (ILCCO; http://ilcco.iarc.fr), with the aim of pooling information and results from all large studies of lung cancer. More details regarding this project are available at http://gentrec.iarc.fr. Nasopharyngeal carcinoma Nasopharyngeal carcinoma (NPC) is a malignancy with a wide range of incidence rates across the world. In most areas, it is rare (e.g. 0.5 cases per 100 000 per year in the United Kingdom), but in certain regions it occurs in an endemic form with an incidence 10- to 40-fold higher. Endemic regions include the southern parts of China, other parts of South-East Asia and the Maghreb (Morocco, Algeria and Tunisia); NPC is also prevalent among Eskimos. We are conducting studies on the role of genes and environmental factors in

the etiology of NPC in Sarawak (Malaysia) and North Africa. NPC incidence is very high in SouthEast Asia. The GEP NPC study aims to be one of the world’s largest studies of NPC. Currently the study sites consist of nationwide efforts in Thailand coordinated by the National Cancer Institute in Bangkok, and in the Sarawak region of Malaysia coordinated by the Kuching General Hospital. We aim to develop studies in Indonesia, Viet Nam and Singapore, and are working with researchers in these areas with this aim in mind. Some of the highest rates of NPC worldwide have been reported to occur among the Bidayuh population of Sarawak State, Malaysia, where age-standardised rates exceed 30 per 100 000 among men. In view of the relative homogeneity of this population, we are conducting studies to investigate both high-risk and moderaterisk susceptibility genes for NPC. For this purpose, approximately 20 high-risk NPC families have been identified and recruited in Sarawak, including one very large multiplex family that contains 19 cases of NPC. Genome-wide linkage analysis is underway in this large multicase family.

Tomsk) with collection of extensive questionnaire information and DNA. Follow-up is underway to identify cancer and other chronic disease outcomes, and future analyses will focus on understanding the causes of the extremely high mortality rates among adults in middle age in this region.

Russian cohort study We are coordinating a large cohort study in Russia along with colleagues in the Cancer Research Centre of Moscow and the Clinical Trials Service Unit of the University of Oxford. Over 100 000 adults have already been recruited from 3 cities in Western Siberia (Barnaul, Bysk and

HPV and head and neck cancer We are undertaking an investigation of HPV in a large series of head and neck cancer patients in collaboration with DKFZ, Heidelberg, Germany.

Other initiatives Pancreatic cancer We are coordinating a large case–control study of pancreatic cancer in Slovakia and the Czech Republic, and are participating in the Pancreatic Cancer Case–Control Consortium (PANC4). Breast cancer We are participating in a large breastcancer case–control study in Thailand with the aim of identifying genetic determinants for breast cancer in this lowincidence country. This study is participating in the breast cancer case– control consortium (BCAC) Cancer in children and young adults We are helping to initiate pilot studies of cancers that occur in childhood and young adulthood.

The GEP Group is grateful to the following for their collaboration in its projects: Agudo Antonio, Barcelona, Spain; Ahrens Wolfgang, Bremen, Germany; Amos Chris, Houston, USA; Arena J. Fernando, Bethesda, MD, USA; Becker Nikolaus, Heidelberg, Germany; Bencko Vladimir, Prague, Czech Republic; Benhamou Simone, Evry, France; Benitez Ortiz Javier, Madrid, Spain; Birch Jillian, Manchester, UK; Blettner Maria, Mainz, Germany; Brewster David, Edinburgh, GB; Buffler Patricia, Berkeley, CA, USA; Canova Cristina, Padova, Italy; Caporaso Neil, Bethesda, USA; Chow Wong-Ho, Bethesda, MD, USA; Clavel Jacqueline, Villejuif, France; Conway David, Glasgow, GB; Cocco Pier Luigi, Cagliari, Italy; Daudt Alexander, Porto Alegre, Brazil; Dawsey Sandy, Rockville, MD, USA; De Camargo Beatriz, Sao Paulo, Brazil; Devi Beena, Kuching, Malaysia ; Easton Doug, Cambridge, UK ; Eluf-Neto José, São Paulo, Brazil; Etzel Carol, Houston, USA; Fabiánová Eleonóra, Banská Bystrica, Slovakia; Fernandez Leticia, Havana, Cuba; Field JK, Liverpool, UK; Foretova Lenka, Brno, Czech Republic; Goldgar David, Salt Lake City, USA; Ha Tam Cam, Singapore; Holcatova Ivana, Prague, Czech Republic; Janout Vladimir, Olomouc, Czech Republic; Karjalainen Tuomo, Brussels, Belgium; Karpov Rotislav,

69

Genetics and Epidemiology Cluster

Tomsk, Russian Federation; Kjaerheim Kristina, Oslo, Norway; Koifman Sergio, Rio de Janeiro, Brazil; Lagiou Pagona, Athens, Greece; Lathrop Mark, Evry, France; Lazarev Aleksander, Barnaul, Russian Federation; Levi José Eduardo, São Paulo, Brazil; Linseisen Jakob, Heidelberg, Germany; Lissowska Jolanta, Warsaw, Poland; Lowry Ray, Newcastle upon Tyne, UK; Lubinski Jan, Szeczcin, Poland ; Malekzadeh Reza, Tehran, Iran; Macfarlane Gary, Manchester, UK; Mates Dana, Bucharest, Romania; Mathew Aleyama, Trivandrum, India; McCartan Bernard, Dublin, Ireland; Menegaux Florence, Villejuif, France; Menezes Ana, Pelotas, Brazil; Merletti Franco, Turin, Italy; Metspalu Andres, Tartu, Estonia; Moukeria Anush, Moscow, Russia; Ng Nawi, Yogyakarta, Indonesia; Nieters Alexandra, Heidelberg, Germany; Ognjanovic Simona, Minneapolis, USA; Olah Edith, Budapest, Hungary; Peto Richard, Oxford, UK; Ribeiro Karina, Sao Paulo, Brazil; Riboli Elio, London, UK; Richiardi Lorenzo, Turin, Italy; Roeleveld Nel, Nijmegen, The Netherlands; Roman Eve, York, UK; Rudnai Peter, Budapest, Hungary; Saito Tomohiro, Tokyo, Japan; Sangrajrang Suleeporn, Bangkok, Thailand; de Sanjosé Silvia, Barcelone, Spain; Seminara Daniela, Bethesda, USA; Seng Chia Kee, Singapore; Simard Jacques, Québec, Canada ; Simonato Lorenzo, Padova, Italy; Staines Anthony, Dublin, Ireland; SzeszeniaDabrowska Neonila, Lodz, Poland; Talamini Renato, Aviano, Italy; Tang Tieng Swee, Kuching, Malaysia ; Thomas Duncan, Los Angeles, USA; Trichopoulos Dimitrios, Athens, Greece; Vendhan Gajalakshmi, Chennai, India; Vineis Paolo, London, UK; Wagner Teresa, Vienna, Austria ; Winn Deborah, Bethesda, USA; Wünsch-Filho Victor, São Paulo, Brazil; Zaridze David, Moscow, Russia; Znaor Ariana, Zagreb, Croatia; Financial support from the following bodies is gratefully acknowledged: European Commission US National Institutes of Health/National Cancer Institute Association for International Cancer Research (AICR) Association pour la Recherche sur le Cancer (ARC) World Cancer Research Fund International, UK Publications Bahrami H, Sadatsafavi M, Pourshams A, Kamangar F, Nouraei M, Semnani S, Brennan P, Boffetta P, Malekzadeh R (2006). Obesity and hypertension in an Iranian cohort study; Iranian women experience higher rates of obesity and hypertension than American women. BMC Public Health; 6:158. Bardin-Mikolajczak A, Lissowska J, Zaridze D, Szeszenia-Dabrowska N, Rudnai P, Fabianova E, Mates D, Navratilova M, Bencko V, Janout V, Fevotte J, Fletcher T, ‘t Mannetje A, Brennan P, Boffetta P (2007). Occupation and risk of lung cancer in Central and Eastern Europe: the IARC multi-center case-control study. Cancer Causes Control; 18: 645-654. Becker N, de Sanjose S, Nieters A, Maynadié M, Foretova L, Cocco PL, Staines A, Alvaro T, Vornanen M, Brennan P, Boffetta P (2007). Birth order, allergies and lymphoma risk: results of the European collaborative research project Epilymph.Leuk Res; 31(10):1365-1372. Besson H, Brennan P, Becker N, de Sanjosé S, Nieters A, Font R, Maynadié M, Foretova L, Cocco PL, Staines A, Vornanen M, Boffetta P (2006). Tobacco smoking, alcohol drinking and Hodgkin’s lymphoma: A European multicentre case-control study (EPILYMPH). Br J Cancer; 95(3): 378-384. Besson H, Brennan P, Becker N, Nieters A, De Sanjosé S, Font R, Maynadié M, Foretova L,

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Cocco PL, Staines A, Vornanen M, Boffetta P Tobacco smoking, alcohol drinking and nonHodgkin’s lymphoma: A European multi-centre case-control study (Epilymph) (2006). Int J Cancer; 119(4): 901-908. Boffetta P, Castaing M, Brennan P (2006). A geographic correlation study of the incidence of pancreatic and other cancers in Whites. European J Epidemiol ; 21 (1): 39-46. Brennan P, Crispo A, Zaridze D, SzeszeniaDabrowska N, Rudnai P, Lissowska J, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, Fletcher T, Boffetta P (2006). High cumulative risk of lung cancer death among smokers and nonsmokers in Central and Eastern Europe. Am J Epidemiol; 164(12): 1233-1241. Brennan P, McKay J, Moore L, Zaridze D, Mukeria A, Szeszenia-Dabrovska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, Chow WH, Rothman N, Chabrier A, Gaborieau V, Odefrey F, Southey M, Hashibe M, Hall J, Boffetta P, Peto J, Peto R, Hung RJ (2007). Uncommon CHEK2 missense variant and reduced risk of tobacco-related cancers: case-control study. Hum Mol Genet; 16(15): 1794-1801. Burdon KP, McKay JD, Wirth G, RussellEggit IM, Dimasi D, Mackey DA, Craig JE (2006). The PITX3 gene in posterior polar congenital cataract in Australia. Mol Vis; 12: 367-371.

Campa D, Hashibe M, Zaridze D, SzeszeniaDabrowska N, Mates IN, Janout V, Holcatova I, Fabianova E, Gaborieau V, Hung RJ, Boffetta P, Brennan P, Canzian F (2007). Association of common polymorphisms in inflammatory genes with risk of developing cancers of the upper aerodigestive tract. Cancer Causes Control ; 18(4): 449-455. Canzian F, McKay JD, Cleveland RJ, Dossus L, Biessy C, Rinaldi S, Landi S, Boillot C, Monnier S, Chajes V, Clavel-Chapelon F, Tehard B, Chang-Claude J, Linseisen J, Lahmann PH, Pischon T, Trichopoulos D, Trichopoulou A, Zilis D, Palli D, Tumino R, Vineis P, Berrino F, Bueno-de-Mesquita HB, van Gils CH, Peeters PH, Pera G, Ardanaz E, Chirlaque MD, Quiros JR, Larranaga N, Martinez-Garcia C, Allen NE, Key TJ, Bingham SA, Khaw KT, Slimani N, Norat T, Riboli E, Kaaks R (2006). Polymorphisms of genes coding for insulin-like growth factor 1 and its major binding proteins, circulating levels of IGF-I and IGFBP-3 and breast cancer risk: results from the EPIC study. Br J Cancer; 94(2): 299-307. Carel R, Olsson AC, Zaridze D, SzeszeniaDabrowska N, Rudnai P, Lissowska J, Fabianova E, Cassidy A, Mates D, Bencko V, Foretova L, Janout V, Fevotte J, Fletcher T, Mannetje AT, Brennan P, Boffetta P (2007). Occupational exposure to asbestos and manmade vitreous fibres and risk of lung cancer: a multicenter case-control study in Europe. Occup Environ Med; 64(8): 502-508.

Genetics Epidemiology Group Casey R, Brennan P, Becker N, Boffetta P, Cocco P, Domingo-Domenech E, Foretova L, Nieters A, de Sanjose S, Staines A, Vornanen M, Maynadie M (2006). Influence of familial cancer history on lymphoid neoplasms risk validated in the large European case-control study epilymph. Eur J Cancer; 42(15): 25702576. Cassidy A, ’t Mannetje A, van Tongeren M, Field JK, Zaridze D, Szeszenia-Dabrowska N, Rudnai P, Lissowska J, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, Fevotte J, Fletcher T, Brennan P, Boffetta P (2007). Occupational exposure to crystalline silica and risk of lung cancer: a multicenter case-control study in Europe. Epidemiol; 18(1): 36-43. Cocco P, Brennan P, Ibba A, de Sanjosè Llongueras S, Maynadié M, Nieters A, Becker N, Ennas MG, Tocco MG, Boffetta P. Plasma polychlorobiphenyl and organochlorine pesticide level and risk of major lymphoma subtypes. Occup Environ Med. (Epub ahead of print 2007) Cox A, Dunning AM, Garcia-Closas M, Balasubramanian S, Reed MW, Pooley KA, Scollen S, Baynes C, Ponder BA, Chanock S, Lissowska J, Brinton L, Peplonska B, Southey MC, Hopper JL, McCredie MR, Giles GG, Fletcher O, Johnson N, Dos Santos Silva I, Gibson L, Bojesen SE, Nordestgaard BG, Axelsson CK, Torres D, Hamann U, Justenhoven C, Brauch H, Chang-Claude J, Kropp S, Risch A, Wang-Gohrke S, Schurmann P, Bogdanova N, Dork T, Fagerholm R, Aaltonen K, Blomqvist C, Nevanlinna H, Seal S, Renwick A, Stratton MR, Rahman N, Sangrajrang S, Hughes D, Odefrey F, Brennan P, Spurdle AB, ChenevixTrench G; The Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer; Beesley J, Mannermaa A, Hartikainen J, Kataja V, Kosma VM, Couch FJ, Olson JE, Goode EL, Broeks A, Schmidt MK, Hogervorst FB, Veer LJ, Kang D, Yoo KY, Noh DY, Ahn SH, Wedren S, Hall P, Low YL, Liu J, Milne RL, Ribas G, Gonzalez-Neira A, Benitez J, Sigurdson AJ, Stredrick DL, Alexander BH, Struewing JP, Pharoah PD, Easton DF; on behalf of the Breast Cancer Association Consortium (2007). A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet; 39(3): 352-358. Corrigendum published in Nat Genet 39(5), page 688, May 2007. De Sanjose S, Benavente Y, Nieters A, Foretova A, Maynadié M, Cocco PL, Staines A, Vornanen M, Boffetta P, Becker N, Alvaro T, Brennan P (2006). Effect of regular use of hair dye on lymphoid neoplasm in Europe. Am J Epidemiol; 164(1): 47-55.

de Sanjosé S, Bosch R, Schouten T, Nieters A, Foretova L, Maynadié M, Cocco PL, Staines A, Becker N, Brennan P, Benavente Y, Boffetta P, Meijer C and Middeldorp J (2007). EpsteinBarr virus infection and risk of lymphoma: Immunoblot analysis of antibody responses against EBV-related proteins in a large series of lymphoma subjects and matched controls. Int J Cancer, 121(8):1806-1812. De Stefani, Boffetta P, Deneo-Pellegrini H, Correa P, Ronco AL, Brennan P, Ferro G, Acosta G, Mendilaharsu M (2007). Nonalcoholic beverages and risk of bladder cancer in Uruguay. BMC Cancer; 7(1): 57. Dikshit RP, Gillio-Tos A, Brennan P, De Marco L, Fiano V, Martinez-Peñuela JM, Boffetta P, Merletti F (2007). Hypermethylation, risk factors, clinical characteristics, and survival in 235 patients with laryngeal and hypopharyngeal cancers. Cancer, 110(8):1745-1751. Durusoy R, Boffetta P, ‘t Mannetje A, Zaridze D, Szeszenia-Dabrowska N, Rudnai P, Lissowska J, Fabianova E, Cassidy A, Mates D, Bencko V, Salajka F, Janout V, Fevotte J, Fletcher T, Brennan P (2006). Lung cancer risk and occupational exposure to meat and live animals. Int J Cancer ; 118: 2543-2547. Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, Struewing JP, Morrison J, Field H, Luben R, Wareham N, Ahmed S, Healey CS, Bowman R; SEARCH collaborators, Meyer KB, Haiman CA, Kolonel LK, Henderson BE, Le Marchand L, Brennan P, Sangrajrang S, Gaborieau V, Odefrey F, Shen CY, Wu PE, Wang HC, Eccles D, Evans DG, Peto J, Fletcher O, Johnson N, Seal S, Stratton MR, Rahman N, Chenevix-Trench G, Bojesen SE, Nordestgaard BG, Axelsson CK, GarciaClosas M, Brinton L, Chanock S, Lissowska J, Peplonska B, Nevanlinna H, Fagerholm R, Eerola H, Kang D, Yoo KY, Noh DY, Ahn SH, Hunter DJ, Hankinson SE, Cox DG, Hall P, Wedren S, Liu J, Low YL, Bogdanova N, Schurmann P, Dork T, Tollenaar RA, Jacobi CE, Devilee P, Klijn JG, Sigurdson AJ, Doody MM, Alexander BH, Zhang J, Cox A, Brock IW, MacPherson G, Reed MW, Couch FJ, Goode EL, Olson JE, Meijers-Heijboer H, van den Ouweland A, Uitterlinden A, Rivadeneira F, Milne RL, Ribas G, Gonzalez-Neira A, Benitez J, Hopper JL, McCredie M, Southey M, Giles GG, Schroen C, Justenhoven C, Brauch H, Hamann U, Ko YD, Spurdle AB, Beesley J, Chen X; kConFab; AOCS Management Group, Mannermaa A, Kosma VM, Kataja V, Hartikainen J, Day NE, Cox DR, Ponder BA (2007). Genome-wide association study identifies novel breast cancer susceptibility loci. Nature; 447(7148): 1087-1093.

Fortuny J, de Sanjose S, Becker N, Maynadié M, Cocco PL, Staines A, Foretova L, Vornanen M, Brennan P, Nieters A, Alvaro T, Boffetta P (2006). Statin use and risk of lymphoid neoplasms: Results from the European casecontrol study Epilymph. Cancer Epidemiol Biomarkers Prev; 15(5): 921-925. Gemignani F, Landi S, Szeszenia-Dabrowska N, Zaridze D, Lissowska J, Rudnai P, Fabianova E, Mates D, Foretova L, Janout V, Bencko V, Gaborieau V, Gioia-Patricola L, Bellini I, Barale R, Canzian F, Hall J, Boffetta P, Hung RJ, Brennan P (2007). Development of lung cancer before the age of 50 : the role of xenobiotic metabolism genes. Carcinogenesis; 28(6): 12871293. Guha N, Boffetta P, Wünsch Filho V, Eluf Neto J, Shangina O, Zaridze D, Curado MP, Koifman S, Matos E, Menezes A, SzeszeniaDabrowska N, Fernandez L, Mates D, Daudt AW, Lissowska J, Dikshit RP, Brennan P (2007). Oral health and risk of squamous cell carcinoma of the head and neck and esophagus: Results of two multicentric case-control studies. Am J Epidemiol;166(10):1159-1173. Hall J, Hashibe M, Boffetta P, Gaborieau V, Moullan N, Chabrier A, Zaridze D, Shangina O, Szeszenia-Dabrowska N, Mates D, Janout V, Fabianova E, Holcatova I, Hung RJ, McKay J, Canzian F, Brennan P (2007). The association of sequence variants in DNA repair and cell cycle genes with cancers of the upper aerodigestive tract. Carcinogenesis; 28(3): 665671. Hashibe M, Boffetta P, Janout V, Zaridze D, Shangina O, Mates D, Szeszenia-Dabrowska N, Bencko V, Brennan P (2007). Esophageal cancer in Central and Eastern Europe: Tobacco and alcohol. Int J Cancer; 120(7): 1518-1522. Hashibe M, Boffetta P, Zaridze D, Shangina O, Szeszenia-Dabrovska N, Mates D, Fabianova E, Rudnai P, Brennan P (2007). The contribution of tobacco and alcohol to the high rates of squamous cell carcinoma of the supraglottis and glottis in Central Europe. Am J Epidemiol: 165(7): 814-820. Hashibe M, Boffetta P, Zaridze D, Shangina O, Szeszenia-Dabrowska N, Mates D, Janout V, Fabiánová E, Bencko V, Moullan N, Chabrier A, Hung R, Hall J, Canzian F, Brennan P (2006). Evidence for an important role of alcohol and aldehyde metabolizing genes in cancers of the upper aerodigestive tract cancer. Cancer Epidemiol Biomarkers Prev; 15(4): 696703. Hayden PJ, Tewari P, Morris DW, Staines A, Crowley D, Nieters A, Becker N, de Sanjosé S, Foretova L, Maynadié M, Cocco PL, Boffetta P,

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Genetics and Epidemiology Cluster Brennan P, Chanock SJ, Browne PV, Lawler M. Variation in DNA repair genes XRCC3, XRCC4, XRCC5 and susceptibility to myeloma. Hum Mol Genet. (Epub ahead of print 2007) Hsu CC, Chow W-H, Boffetta P, Moore L, Zaridze D, Mukeria A, Janout V, Kolarova H, Bencko V, Navratilova M, SzeszeniaDabrovska N, Mates D, Brennan P (2007). Dietary risk factors for kidney cancer in Eastern and Central Europe. Am J Epidemiol; 166(1): 62-70. Hung RJ, Boffetta P, Canzian F, Moullan N, Szeszenia-Dabrowska N, Zaridze D, Lissowska J, Rudnai P, Fabianova E, Mates D, Foretova L, Janout V, Bencko V, Chabrier A, Landi S, Gemignani F, Hall J, Brennan P (2006). Sequence Variants in Cell Cycle Control Pathway, X-ray exposure, and Lung Cancer Risk: A Multicenter Case-Control Study in Central Europe. Cancer Res; 66 (16): 82808286. Hung RJ, Hashibe M, McKay J, Gaborieau V, Szeszenia-Dabrovska N, Zaridze D, Lissowska J, Rudnai P, Fabianova E, Mates I, Foretova L, Janout V, Bencko V, Chabrier A, Moullan N, Canzian F, Hall J, Boffetta P, Brennan P (2007). Folate related genes and the risk of tobaccorelated cancers in Central Europe. Carcinogenesis; 28(6): 1334-1340. Hung RJ, Moore L, Boffetta P, Feng B-J, Toro JR, Rothman N, Zaridze D, Navratilova M, Bencko V, Janout V, Kollarova H, SzeszeniaDabrowska N, Mates D, Chow W-H, Brennan P (2007). Family history and the risk of kidney cancer: a multicenter case-control study in Central Europe. Cancer Epidemiol Biomarkers Prev; 16(6): 1287-1290. Hung RJ, Zhang ZF, Rao, JY, Pantuck A, Reuter VE, Heber D, Lu QY (2006). Protective effects of plasma carotenoids on the risk of bladder cancer. J. Urol; 176(3): 1192-1197. Johansson M, McKay JD, Stattin P, Canzian F, Boillot C, Wiklund F, Adami H, Bälter K, Grönberg H, Kaaks R (2007). Comprehensive evaluation of genetic variation in the IGF1 gene and risk of prostate cancer. Int J Cancer; 120(3): 539-542. Kellen E, Hemelt M, Broberg K, Golka K, Kristensen VN, Hung RJ, Matullo G, Mittal RD, Porru S Povey A, Schulz WA, Shen J, Buntinx F, Zeegers MP, Taioli E (2007). Pooled Analysis and Meta-analysis of Glutathione Stransferase P1 Ile 105Val and Bladder Cancer: a HuGE GSEC Review. Am J Epidemiol; 165(11): 1221-1230.

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Landi S, Gemignani F, Canzian F, Gaborieau V, Barale R, Landi D, Szeszenia-Dabrowska N, Zaridze D, Lissowska J, Rudnai P, Fabianova E, Mates D, Foretova L, Janout V, Bencko V, Gioia-Patricola L, Hall J, Boffetta P, Hung RJ, Brennan P (2006). DNA repair and cell cycle control genes and the risk of young-onset lung cancer. Cancer Res; 66(22): 11062-11069.

Mounawar M, Mukeria A, Le Calvez F, Hung RJ, Renard H, Cortot A, Bollart C, Zaridze D, Brennan P, Boffetta P, Brambilla E, Hainaut P (2007). Patterns of EGFR, HER2, TP53, and KRAS mutations of p14arf expression in nonsmall cell lung cancers in relation to smoking history. Cancer Res; 67(12): 5667-5672.

Mansour N, Kamel MH, Kelleher M, Aquilina K, Thornton J, Brennan P, Bolger C (2007). Resolution of cranial nerve paresis after endovascular management of cerebral aneurysms. Surg Neurol; 68(5):500-504.

Nieters A, Kallinowski B, Brennan P, Ott M, Maynadie M, Benavente Y, Foretova L, Cocco PL, Staines A, Vornanen M, Whitby D, Boffetta P, Becker N, De Sanjose S (2006). Hepatitis C and risk of lymphoma: results of the European multicenter case-control study EPILYMPH. Gastroenterol; 131(6): 1879-1886.

Malekshah AF, Kimiagar M, Saadatian-Elahi M, Pourshams A, Nouraie M, Goglani G, Hoshiarrad A, Sadatsafavi M, Golestan B, Yoonesi A, Rakhshani N, Fahimi S, Nasrollahzadeh D, Salahi R, Ghafarpour A, Semnani S, Steghens JP, Abnet CC, Kamangar F, Dawsey SM, Brennan P, Boffetta P, Malekzadeh R (2006). Validity and reliability of a new food frequency questionnaire compared to 24 h recalls and biochemical measurements: pilot phase of Golestan cohort study of esophageal cancer. European J Clin Nutrition; 60(8):971-977. Marques FS, Koifman S, Koifman RJ, Boffetta P, Brennan P, Hatagima A (2006). Influence of CYP1A1, CYP2E1, GSTM3 and NAT2 genetic polymorphisms in oral cancer susceptibility : Results from a case-control study in Rio de Janeiro. Oral Oncol; 42(6):632-637. McKay J, Kaaks R, Johansson M, Biessy C, Wiklund F, Bälter K, Adami H, Boillot C, Gioia-Patricola L, Canzian F, Stattin P, Grönberg H (2007). Haplotype-based analysis of common variation in the Growth Hormone Receptor gene and prostate cancer risk. Cancer Epidemiol Biomarkers Prev; 16(1): 169-173. McLaren J, Rowe M, Brennan P (2007). Epstein-Barr virus induces a distinct form of DNA-bound STAT1 compared with that found in interferon-stimulated B lymphocytes. J Gen Virol; 88(Pt 7):1876-1886. Mellemkjaer L, Friis S, Olsen JH, Scélo G, Hemminki K, Tracey E, Andersen A, Brewster DH, Pukkala E, McBride ML, Kliewer EV, Tonita JM, Chia KS, Pompe-Kirn V, Martos C, Jonasson JG, Boffetta P, Brennan P (2006). Risk of second cancer among women with breast cancer. Int J Cancer; 118: 2285-2292. Moore T, Brennan P, Becker N, de Sanjosé S, Maynadié M, Foretova L, Cocco P, Staines A, Nieters A, Font R, ‘t Mannetje A, BenhaimLuzon V, Boffetta P (2007). Occupational exposure to meat and risk of lymphoma: A multicenter case-control study from Europe. Int J Cancer; 121(12):2761-6.

Richiardi L, Scelo G, Boffetta P, Hemminki K, Pukkala E, Olsen JH, Weiderpass E, Tracey E, Brewster DH, McBride ML, Kliewer EV, Tonita JM, Pompe-Kirn V, Kee-Seng C, Jonasson JG, Martos C, Brennan P (2007). Second malignancies among survivors of germ-cell testicular cancer: a pooled analysis between 13 cancer registries. Int J Cancer; 120(3): 623-631. Riska A, Pukkala E, Scelo G, Mellemkjaer L, Hemminki K, Weiderpass E, McBride ML, Pompe-Kirn V, Tracey E, Brewster DH, Kliewer EV, Tonita JM, Kee-Seng C, Jonasson JG, Martos C, Boffetta P, Brennan P (2007). Second primary malignancies in females with primary fallopian tube cancer. Int J Cancer; 120(9): 2047-2051. Rothman N, CF Skibola, SS Wang, G Morgan, Q Lan, MT Smith, JJ Spinelli, E Willett, S De Sanjosé, P Cocco, SI Berndt, P Brennan, A Brooks-Wilson, S Wacholder, N Becker, P Hartge, T Zheng, E Roman, EA Holly, P Boffetta, B Armstrong, W Cozen, M Linet, FX Bosch, MG Ennas, TR Holford, RP Gallagher, S Rollinson, PM Bracci, JR Cerhan, D Withby, PS Moore, B Leaderer, A Lai, C Spink, S Davis, R Bosch, A Scarpa, WY Zhang, RK Severson, M Yeager, S Chanock, A Nieters (2006). Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph Consortium. Lancet Oncol; 7 (1): 27-38. Sandeep T, Strachan MJW, Reynolds RM, Brewster DH, Scélo G, Pukkala E, Hemminki K, Andersen A, Tracey E, Friis S, McBride ML, K-S Chia, Pompe-Kirn V, Kliewer EV, Tonita JM, Jonasson JG, Martos C, Boffetta P, Brennan P (2006). Second primary cancers in thyroid cancer patients : a multinational record linkage study. J Clin Endocrinol and Metab; 91(5):1819-1825. Sangrajrang S, Schmezer P, Burkholder I, Boffetta P, Brennan P, Woelfelschneider A, Bartsch H, Wiangnon S, Cheisilpa A, Popanda O. The XRCC3 Thr241Met polymorphism

Genetic Epidemiology Group and breast cancer risk: a case-control study in a Thai population. Biomarkers; 12(5):523-32. Sangrajrang S, Schmezer P, Burkholder I, Waas P, Boffetta P, Brennan P, Bartsch H, Wiangnon S, Popanda O. Polymorphisms in three base excision repair genes and breast cancer risk in Thai women. Breast Cancer Res Treat. (Epub ahead of print 2007) Sapkota A, Gajalakshmi V, Jetly DH, Roychowdhury S, Dikshit RP, Brennan P, Hashibe M, Boffetta P (2007). Smokeless tobacco and increased risk of hypopharyngeal and laryngeal cancers: a multicentric casecontrol study from India. Int J Cancer; 121(8):1793-1798. Scelo G, Boffetta P, Autier P, Hemminki K, Pukkala E, Olsen JH, Weiderpass E, Tracey E, Brewster DH, McBride ML, Kliewer EV, Tonita JM, Pompe-Kirn V, Chia KS, Jonasson JG, Martos C, Giblin M, Brennan P (2007). Associations between ocular melanoma and other primary cancers: an international population-based study. Int J Cancer; 120(1): 152-159. Scelo G, Boffetta P, Corbex M, Chia KS, Hemminki K, Friis S, Pukkala E, Weiderpass E, McBride ML, Tracey E, Brewster DH, Pompe-Kirn V, Kliewer EV, Tonita JM, Martos C, Jonasson JG, Brennan P (2007). Second primary cancers in patients with nasopharyngeal carcinoma: a pooled analysis of 13 cancer registries. Cancer Causes Control; 18(3): 269-278. Scelo G, Boffetta P, Hemminki K, Pukkala E, Olsen JH, Andersen A, Tracey E, Brewster DH, McBride ML, Kliewer EV, Tonita JM, PompeKirn V, Chia KS, Jonasson JG, Martos C, Colin D, Brennan P (2006). Associations between small intestine cancer and other primary cancers: An international population-based study. Int J Cancer; 118:189-196.

Scelo G, Brennan P (2007). The epidemiology of Bladder and kidney cancer. Nat Clin Pract Urol; 4(4): 205-217. Shangina O, Brennan P, Szeszenia-Dabrowska N, Mates D, Fabianova E, Fletcher T, t’Mannetje A, Boffetta P, Zaridze D (2006). Occupational exposure and laryngeal and hypopharyngeal cancer risk in Central and Eastern Europe. Am J Epidemiol ; 164: 367-375. Shen M, Boffetta, P. Olsen JH, Andersen A, Hemminki K, Pukkala E, Tracey E, Brewster DH, McBride ML, Pompe-Kirn V, Kliewer EV, Tonita JM, Chia KS, Martos C, Jonasson JG, Colin D, Scélo G, Brennan P (2006). Pooled analysis of second primary pancreatic cancer. Am J Epidemiol; 163: 502-511. Sinilnikova O, McKay JD, Tavtigian SV, Canzian F, DeSilva D, Biessy C, Monnier S, Dossus L, Boillot C, Gioia L, Hughes D, Jensen M, Overvad K, Tjonneland A, Olsen A, Clavel-Chapelon F, Chajès V, Joulin V, Linseisen J, Chang-Claude J, Boeing H, Dahm S, Trichopoulou A, Trichopoulos D, Koliva M, Palli D, Panico S, Berrino F, R.Tumino, Vineis P, Bueno-de-Mesquita H, Peeters P,van Gils C, Lund E, Pera G, Quirós J, Dorronsoro M, Martínez García C, Tormo M, Ardanaz E, Hallmans G, Lenner P, Manjer J, Riboli E, Lenoir GM, and Kaaks R (2007). HaplotypeBased Analysis of Common Variation in the Acetyl-CoA Carboxylase alpha Gene and Breast Cancer Risk: a Case-Control Study Nested within the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiol Biomarkers Prev; 16(3): 409-415. The Breast Cancer Association Consortium (2006). Commonly studied single-nucleotide polymorphisms and breast cancer: results from the Breast Cancer Association Consortium. J Nat Cancer Inst; 98(19): 1382-1396. Thomson R, Quinn S, McKay J, Silver J, Bahlo M, FitzGerald L, Dickinson J,

Stankovich J (2007). The advantages of very dense marker sets for linkage analysis with large families. Hum Genet; 121(3-4): 459468. Tuohimaa P, Pukkala E, Scelo G, Olsen JH, Brewster DH, Hemminki K, Tracey E, Weiderpass E, Kliewer EV, Pompe-Kirn V, McBride ML, Martos C, Chia KS, Tonita JM, Jonasson JG, Boffetta P, Brennan P (2007). Does solar exposure, as indicated by the nonmelanoma skin cancers, protect from solid cancers: Vitamin D as a possible explanation. Eur J Cancer; 43(11):1701-1712. van Balen E, Font R, Cavalle N, Font L, Garcia-Villanueva M, Benavente Y, Brennan P, de Sanjose S (2006). Exposure to non-arsenic pesticides is associated with lymphoma among farmers in Spain. Occup Environ Med; 63(10): 663-668. Wang SS, Slager SL, Brennan P, Holly EA, De Sanjose S, Bernstein L, Boffetta P, Cerhan JR, Maynadie M, Spinelli JJ, Chiu BC, Cocco P, Mensah F, Zhang Y, Nieters A, Dal Maso L, Bracci PM, Costantini AS, Vineis P, Severson RK, Roman E, Cozen W, Weisenburger D, Davis S, Franceschi S, La Vecchia C, Foretova L, Becker N, Staines A, Vornanen M, Zheng T, Hartge P (2007). Family history of hematopoietic malignancies and risk of nonHodgkin lymphoma (NHL): a pooled analysis of 10,211 cases and 11,905 controls from the International Lymphoma Epidemiology Consortium (InterLymph). Blood; 109(8): 3479-3488. Zeka A, Mannetje A, Zaridze D, SzeszeniaDabrowska N, Rudnai P, Lissowska J, Fabianova E, Mates D, Bencko V, Navratilova M, Cassidy A, Janout V, Travier N, Fevotte J, Fletcher T, Brennan P, Boffetta P (2006). Lung cancer and occupation in nonsmokers: a multicenter case-control study in Europe. Epidemiol; (6): 615-623.

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Genetic Susceptibility Group (GCS) Head Dr Sean Tavtigian Secretary Mrs Antoinette Trochard Scientists Dr Florence Le Calvez-Kelm Dr Fabienne Lesueur Dr Melissa Southey (until August 2006) Technical Assistants Ms Nathalie Forey

The Genetic Susceptibility Group (GCS) is made up of two Teams, the Genetic Services Platform Team (GSP) and the High-Risk Genes Team (HRG). GSP focuses on providing genotyping, mutation scanning and resequencing services for cancer susceptibility research projects throughout IARC. HRG focuses on discovery and/or characterisation of highrisk and intermediate-risk cancer susceptibility genes. The GSP Team and its automated high throughput genetic platform The GSP Team is now running an efficient automated platform for relatively highthroughput genotyping, mutation scanning and resequencing. The platform integrates several multipurpose liquid handling robots into its laboratory processes and relies on a Laboratory Information Management System (LIMS) to track the progress of samples through the laboratory workflows. The combination of robots and LIMS has improved the efficiency and quality of the work by reducing potential human error, accelerating the throughput of analysis and enabling sample tracking activities that are very difficult to perform by hand. The main workflows supported by the platform are TAQMAN genotyping, High Resolution Melt curve analysis (HRM) for mutation scanning, and resequencing for 74

Mrs Isabelle Gilibert Mrs Lydie Gioia Mrs Sandrine McKay-Chopin Ms Jocelyne Michelon Ms Catherine Voegele Mrs C. Boillot (until August 2006) Ms L. Barjhoux (until March 2006) Mr F. Odefrey (until December 2006) Mrs. S. Pauly (until October 2007)

Postdoctoral fellows Dr J. Ahmad (from November 2007) Dr D. Babikyan (until October 2007) Dr S. Garritano (from April 2005) Dr L. Jordheim (from January 2006) Students Ms B.T.T. Nguyen (from September 2005) Mr M. Vallée (August 2007)

Visiting scientists Dr Graham Byrnes (May 2006June 2007) Dr L. De Carvalho (until January 2007)

mutation identification. Recent improvements have been brought to the mutation screening workflow and to the LIMS to allow HRM in a 384-well format, dramatically improving the throughput of the analysis. GSP has also validated the use of HRM analysis for high throughput and inexpensive genotyping when TAQMAN assays failed for some SNPs. The flexibility of GSP's platform also allows it to support additional analyses including microsatellite genotyping for linkage analysis, segregation analysis, or LOH studies, and Multiplex Ligation-dependent Probe Amplification (MLPA) for the identification of germline copy number changes in various genes. In order to standardise and harmonise data management within the Agency, IARC acquired, at the end of 2006, an ABI SQL* LIMS programming package. Under development as a collaboration between GSP, ITS, and LIR, this new LIMS should be operational for the first high-throughput workflows at the end of 2007. Ongoing development will allow all IARC groups to benefit from the new LIMS in the near future. Not only will the new LIMS provide a useful tool to track the progress of samples through specific laboratory workflows, but it will also give a global overview of sample availability, flows and processed analyses within the different IARC groups.

Large-scale genotyping projects During 2006–2007, GSP’s genotyping platform contributed to several of IARC's large genetic epidemiology projects. These included GEP projects focusing on genetic susceptibility to tobacco- and alcoholrelated cancers in Central Europe and GEP/ GEE projects investigating alcoholrelated cancers and genetic susceptibility in Western Europe (ARCAGE) and in Latin America. The genotyping platform also contributed to several EPIC projects, including investigations of the insulin-like growth factor pathway and growth hormone receptor pathway in breast and prostate cancer, and the contribution of genetic variation in the fatty acid biosynthetic pathway to risk of breast cancer. In addition, the genotyping platform contributed to an ICE project examining the genetics of bacterial-host interaction in gastric cancer. Although the GSP genotyping platform does not yet have the capacity to execute genomewide SNP association (GWA) studies, we have contributed to the large-scale replication studies that are required to distinguish between truepositive and false-positive results flowing from GWA studies. These are exemplified by our contributions to the Breast Cancer Association Consortium's massive studies of candidate risk-SNPs in breast cancer

Genetic Susceptibility Group

susceptibility, which arrived at the conclusion that common variants in genes such as CASP8, TGFB1, and FGFR2 do make modest contributions to the risk of breast cancer, and, more generally, that cancer "polygenes" do exist. Mutation screening projects The introduction of HRM analysis has improved our throughput for mutation screening and resequencing. Our mutation screening platform has been used for sequence variant discovery in the context of two EPIC projects, the first one investigating the contribution of genetic variation in the fatty acid biosynthetic pathway to risk of breast cancer and the second one in evaluating the contribution of genetic variation in the mTOR (mammalian target of rapamycin) pathway to susceptibility to prostate cancer. We have also exhaustively mutation-screened the TP53 locus — promoter, exons, and introns, including a MLPA scan for duplications and deletions — in a series of 50 Li-Fraumeni patients. This work was completed in 2007 and should lead to a number of publications in 2008. The HRG Team searches for susceptibility genes in common cancers Germline mutations in the BRCA1 and BRCA2 genes explain only a minority of the excess familial aggregation observed for premenopausal breast cancer. Via extensive international collaboration, IARC contributed linkage data to the largest linkage analysis to date searching for additional breast cancer susceptibility genes. This analysis and many other recent smaller studies have suggested that there may be several breast cancer susceptibility genes yet to be identified (rather than “BRCA3” alone explaining all of the residual familial breast cancer aggregations). Our analysis, when restricted to families with at least four cases of breast cancer diagnosed before the age of 50 years found a LOD score of 2.40 on Chromosome 2p. There are many candidate breast cancer susceptibility genes in this region, including the DNA mismatch repair (MMR) gene MSH2. Although breast cancer is not regarded as part of the tumour spectrum of Hereditary Non Polyposis Colorectal Cancer

(HNPCC), MMR dysfunction is known to play a role in the progression of a proportion of breast cancers which raised a new question — thus we sought to investigate the possibility that mutations in MSH2 might explain the multiple cases of breast cancer in some families that were included in the international genome-wide scan. Extensive screening of 59 multiplecase breast cancer families did not identify any coding region mutations or larger genomic alterations in MSH2 that might implicate MSH2 as a breast cancer susceptibility gene. Molecular pathology of breast cancer diagnosed in young women We and others have observed that tumours arising in carriers of BRCA1 germline mutations have a distinctive morphological appearance. In collaboration with the BreastCFR we have identified 700 cases of early-onset breast cancer that have this distinctive BRCA1-associated morphology and/or a very strong family history of breast cancer. We are currently assessing what proportion of these cases carry BRCA1 mutations that can be identified using routine approaches and by applying additional screening methods to detect other types of BRCA1 mutations and mutations in regulatory regions and BRCA1 regulating elements that have not been previously considered as possible explanations for BRCA1 silencing. In a study of young Brazilian women affected with breast cancer we have evaluated the distribution of molecular subtypes of breast cancer using an immunohistochemical panel of biomarkers on tissue microarray and loss of heterozygosity (LOH) analysis within BRCA1. In our study, the basal-like tumour was the second most frequent molecular type (21%) among young Brazilian women and was the most frequent subtype to display LOH at the BRCA1 locus. These studies will be relevant to every woman who is diagnosed with early-onset breast cancer. They will allow the treating physicians to estimate the likelihood of each women being a carrier of a BRCA1 mutation at the time of diagnosis, based on specific aspects of the woman’s tumour morphology and independent of her

family history of breast cancer and might support the introduction of routine referral of young women identified as being at increased risk of carrying a BRCA1 mutation to genetic clinics and counselling. Unclassified variants in BRCA1 and BRCA2 Mutation screening of BRCA1 and BRCA2 has become a routine clinical cancer genetics procedure in North America and is approaching routine in Western Europe. Under the ascertainment criteria generally required for testing, 10– 20% of the tested population are found to carry a clearly deleterious genetic variant in one of the two genes. However, a similar fraction of patients are found to carry an unclassified variant (UV) with no clearly deleterious variant. The detection of UVs, which are mostly rare missense substitutions, creates problems for everyone from the testing labs to cancer genetics counsellors and patients. At a Breast Cancer Information Core (BIC) meeting in 2000, members of the BIC steering committee proposed a strategy for combining several different types of data to analyse and classify BRCA1 and BRCA2 UVs. That proposal led, four years later, to an integrated method of genetic variant analysis that combined 5 components: (1) segregation in pedigrees, (2) personal and family cancer history, (3) co-occurrence with known clearly deleterious variants, (4) evolutionary conservation of the position in BRCA1 or BRCA2 of the unclassified missense substitution of interest, and (5) the physicochemical difference between the wild-type and mutant amino acid. A key feature of the integrated method is that its output is a single likelihood ratio expressing odds that a sequence variant of interest is comparable to a truncating variant in BRCA1 or BRCA2. Over the last two years, this integrated method has been improved in several ways. First, tumour morphology and immunohistochemistry have been added to the list of components integrated in the method. Second, the method has been applied to entire databases of UVs in order to systematically reclassify larger numbers of variants as either clinically important or neutral/of little clinical importance. Third, the measures of evolutionary conservation 75

Genetics and Epidemiology Cluster

and amino acid physicochemical difference have been improved and are now available through our Align-GVGD website (http://agvgd.iarc.fr). Finally, the original likelihood expression has been reformulated as (prior probability x

likelihood = posterior probability). In this reformulation, the combination of position in the protein, evolutionary conservation and amino acid physicochemical difference provide a prior probability for the vast majority of all missense substitutions.

Consequently, the integrated method for analysis of UVs has become both more informative and more powerful than it was when first described.

The GCS Group is grateful to the following for their collaboration in its projects: I. Andrulis, Toronto, Canada; A.-L. Børresen-Dale, Montebello, Norway; G. Byrnes, Victoria, Australia; G. Chenevix-Trench, Melbourne, Australia; F. Couch, Rochester, MN, USA; A.M. Deffenbaugh Salt Lake City, UT, USA; P. Devilee, Leiden, Netherlands; C. Dumontet, Lyon, France; D. Easton, Cambridge, UK; E. Friedman, Tel-Hashomer, Israel; D. Goldgar, Salt Lake City, USA; J.L. Hopper, Melbourne, Australia; E. John, Fremont, CA, USA; G. Mann, Sydney, Australia; A. Monteiro, Tampa, FL, USA; S. Neuhausen, Irvine, CA, USA; S. Plon, Houston, TX, USA; P.A. Samollow, College Station, TX, USA; J. Simard, Quebec, Canada; O. Sinilnikova, Lyon, France; N. Sodha, Sutton, United Kingdom; M.R. Stratton, Sutton, UK; A. Thomas, Salt Lake City, UT, USA; I. Tomlinson, London , UK; T. van Wezel, Leiden, Netherlands ; The Breast Cancer Information Consortium; The Australian Breast Cancer Family Study ; The Breast CFR (NCI, USA); The CoReGenes Investigators; The International BRCA3 Linkage Consortium; Financial support from the following bodies is gratefully acknowledged: The Canadian Institutes of Health Research; The United States Department of Defence; The United States National Cancer Institute; The Mayo Clinic, Rochester, MN, USA. Publications Alsop K, Mead L, Smith LD, Royce SG, Tesoriero AA, Young JP, Haydon A, Grubb G, Giles GG, Jenkins MA, Hopper JL, Southey MC (2006). Low somatic K-ras mutation frequency in colorectal cancer diagnosed under the age of 45 years. Eur J Cancer; 42: 1357-1361. Apicella C, Dowty J, Dite G, Jenkins M, Senie R, Daly M, Andrulis I, John E, Buys S, Li F, Glendon G, Chung W, Ozcelik H, Miron A, Kotar K, Southey M, Foulkes W, Hopper J (2007). Validation study of the lambda model for predicting the BRCA1 or BRCA2 mutation carrier status of North American Ashkenazi Jewish women. Clin Genet; 72: 87-97. Avard D, Bridge P, Bucci LM, Chiquette J, Dorval M, Durocher F, Easton D, Godard B, Goldgar D, Knoppers BM, Laframboise R, Lesperance B, Plante M, Tavtigian SV, Vezina H, Wilson B, Simard J (2006). Partnering in oncogenetic research—the INHERIT BRCAs experience: opportunities and challenges. Fam Cancer; 5: 3-13. Bane AL, Beck JC, Bleiweiss I, Buys SS, Catalano E, Daly MB, Giles G, Godwin AK, Hibshoosh H, Hopper JL, John EM, Layfield L, Longacre T, Miron A, Senie R, Southey MC, West DW, Whittemore AS, Wu H, Andrulis IL, O’Malley FP (2007). BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecu76

lar profiles from tissue microarrays. Am J Surg Pathol; 31: 121-128. Bernstein JL, Teraoka S, Southey MC, Jenkins MA, Andrulis IL, Knight JA, John EM, Lapinski R, Wolitzer AL, Whittemore AS, West D, Seminara D, Olson ER, Spurdle AB, Chenevix-Trench G, Giles GG, Hopper JL, Concannon P (2006). Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.1066-6T>G (IVS10-6T>G) from the Breast Cancer Family Registry. Hum Mutat; 27: 1122-1128.

Allen NE, Key TJ, Bingham SA, Khaw KT, Slimani N, Norat T, Riboli E, Kaaks R (2006). Polymorphisms of genes coding for insulin-like growth factor 1 and its major binding proteins, circulating levels of IGF-I and IGFBP-3 and breast cancer risk: results from the EPIC study. Br J Cancer; 94: 299-307. Cardis E, Hall J, Tavtigian SV (2007). Identification of women with an increased risk of developing radiation-induced breast cancer. Breast Cancer Res; 9: 106.

Brennan P, McKay J, Moore L, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, Chow WH, Rothman N, Chabrier A, Gaborieau V, Odefrey F, Southey M, Hashibe M, Hall J, Boffetta P, Peto J, Peto R, Hung RJ (2007). Uncommon CHEK2 mis-sense variant and reduced risk of tobacco-related cancers: case control study. Hum Mol Genet; 16: 1794-1801.

Chenevix-Trench G, Healey S, Lakhani S, Waring P, Cummings M, Brinkworth R, Deffenbaugh AM, Burbidge LA, Pruss D, Judkins T, Scholl T, Bekessy A, Marsh A, Lovelock P, Wong M, Tesoriero A, Renard H, Southey M, Hopper JL, Yannoukakos K, Brown M, Easton D, Tavtigian SV, Goldgar D, Spurdle AB (2006). Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance. Cancer Res; 66: 2019-2027.

Canzian F, McKay JD, Cleveland RJ, Dossus L, Biessy C, Rinaldi S, Landi S, Boillot C, Monnier S, Chajes V, Clavel-Chapelon F, Tehard B, Chang-Claude J, Linseisen J, Lahmann PH, Pischon T, Trichopoulos D, Trichopoulou A, Zilis D, Palli D, Tumino R, Vineis P, Berrino F, Bueno-de-Mesquita HB, van Gils CH, Peeters PH, Pera G, Ardanaz E, Chirlaque MD, Quiros JR, Larranaga N, Martinez-Garcia C,

Cox A, Dunning AM, Garcia-Closas M, Balasubramanian S, Reed MW, Pooley KA, Scollen S, Baynes C, Ponder BA, Chanock S, Lissowska J, Brinton L, Peplonska B, Southey MC, Hopper JL, McCredie MR, Giles GG, Fletcher O, Johnson N, Dos SS, I, Gibson L, Bojesen SE, Nordestgaard BG, Axelsson CK, Torres D, Hamann U, Justenhoven C, Brauch H, ChangClaude J, Kropp S, Risch A, Wang-Gohrke S,

Genetic Susceptibility Group Schurmann P, Bogdanova N, Dork T, Fagerholm R, Aaltonen K, Blomqvist C, Nevanlinna H, Seal S, Renwick A, Stratton MR, Rahman N, Sangrajrang S, Hughes D, Odefrey F, Brennan P, Spurdle AB, Chenevix-Trench G, Beesley J, Mannermaa A, Hartikainen J, Kataja V, Kosma VM, Couch FJ, Olson JE, Goode EL, Broeks A, Schmidt MK, Hogervorst FB, Van’t Veer LJ, Kang D, Yoo KY, Noh DY, Ahn SH, Wedren S, Hall P, Low YL, Liu J, Milne RL, Ribas G, Gonzalez-Neira A, Benitez J, Sigurdson AJ, Stredrick DL, Alexander BH, Struewing JP, Pharoah PD, Easton DF (2007). A common coding variant in CASP8 is associated with breast cancer risk. Nat Genet; 39: 352-358. Durocher F, Labrie Y, Soucy P, Sinilnikova O, Labuda D, Bessette P, Chiquette J, Laframboise R, Lepine J, Lesperance B, Ouellette G, Pichette R, Plante M, Tavtigian SV, Simard J (2006). Mutation analysis and characterization of ATR sequence variants in breast cancer cases from high-risk French Canadian breast/ovarian cancer families. BMC Cancer; 6: 230. Easton DF, Deffenbaugh AM,Pruss D,Frye C,Allen-Brady K,Tavtigian SV,Monteiro ANA,Iversen ES,Couch FJ,Goldgar DE. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer predisposition genes. Am J Hum Genet, In press Easton DF, Pooley KA, Dunning AM, Pharoah PD, Thompson D, Ballinger DG, Struewing JP, Morrison J, Field H, Luben R, Wareham N, Ahmed S, Healey CS, Bowman R, Meyer KB, Haiman CA, Kolonel LK, Henderson BE, Le ML, Brennan P, Sangrajrang S, Gaborieau V, Odefrey F, Shen CY, Wu PE, Wang HC, Eccles D, Evans DG, Peto J, Fletcher O, Johnson N, Seal S, Stratton MR, Rahman N, ChenevixTrench G, Bojesen SE, Nordestgaard BG, Axelsson CK, Garcia-Closas M, Brinton L, Chanock S, Lissowska J, Peplonska B, Nevanlinna H, Fagerholm R, Eerola H, Kang D, Yoo KY, Noh DY, Ahn SH, Hunter DJ, Hankinson SE, Cox DG, Hall P, Wedren S, Liu J, Low YL, Bogdanova N, Schurmann P, Dork T, Tollenaar RA, Jacobi CE, Devilee P, Klijn JG, Sigurdson AJ, Doody MM, Alexander BH, Zhang J, Cox A, Brock IW, MacPherson G, Reed MW, Couch FJ, Goode EL, Olson JE, Meijers-Heijboer H, van den OA, Uitterlinden A, Rivadeneira F, Milne RL, Ribas G, Gonzalez-Neira A, Benitez J, Hopper JL, McCredie M, Southey M, Giles GG, Schroen C, Justenhoven C, Brauch H, Hamann U, Ko YD, Spurdle AB, Beesley J, Chen X, Mannermaa A, Kosma VM, Kataja V, Hartikainen J, Day NE, Cox DR, Ponder BA (2007). Genome-wide association study identifies novel breast cancer susceptibility loci. Nature; 447: 1087-1093.

Haile RW, Thomas DC, McGuire V, Felberg A, John EM, Milne RL, Hopper JL, Jenkins MA, Levine AJ, Daly MM, Buys SS, Senie RT, Andrulis IL, Knight JA, Godwin AK, Southey M, McCredie MR, Giles GG, Andrews L, Tucker K, Miron A, Apicella C, Tesoriero A, Bane A, Pike MC, Whittemore AS (2006). BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50. Cancer Epidemiol Biomarkers Prev; 15: 1863-1870. Hammet F, George J, Tesoriero AA, Jenkins MA, Schroen C, Smith L, Grabosch-Meehan A, Dite G, McCredie MR, Giles GG, Tavtigian SV, Hopper JL, Southey MC (2007). Is BRCA2 c.9079 G > A a predisposing variant for early onset breast cancer? Breast Cancer Res Treat; Hayes VM, Severi G, Padilla EJ, Morris HA, Tilley WD, Southey MC, English DR, Sutherland RL, Hopper JL, Boyle P, Giles GG (2007). 5alpha-Reductase type 2 gene variant associations with prostate cancer risk, circulating hormone levels and androgenetic alopecia. Int J Cancer; 120: 776-780. Hayes VM, Severi G, Southey MC, Padilla EJ, English DR, Hopper JL, Giles GG, Sutherland RL (2006). Macrophage inhibitory cytokine-1 H6D polymorphism, prostate cancer risk, and survival. Cancer Epidemiol Biomarkers Prev; 15: 1223-1225. Jenkins MA, Baglietto L, Dowty JG, Van Vliet CM, Smith L, Mead LJ, Macrae FA, St John DJ, Jass JR, Giles GG, Hopper JL, Southey MC (2006). Cancer risks for mismatch repair gene mutation carriers: a population-based early onset case-family study. Clin Gastroenterol Hepatol; 4: 489-498. Jenkins MA, Southey MC, Giles GG, Hopper JL (2007). Rationale for, and approach to, studying modifiers of risk in persons with a genetic predisposition to colorectal cancer. Curr Oncol Rep; 9: 202-207. John EM, Phipps AI, Knight JA, Milne RL, Dite GS, Hopper JL, Andrulis IL, Southey M, Giles GG, West DW, Whittemore AS (2007). Medical radiation exposure and breast cancer risk: findings from the Breast Cancer Family Registry. Int J Cancer; 121: 386-394. Johnson N, Fletcher O, Palles C, Rudd M, Webb E, Sellick G, Dos SS, I, McCormack V, Gibson L, Fraser A, Leonard A, Gilham C, Tavtigian SV, Ashworth A, Houlston R, Peto J (2007). Counting potentially functional variants in BRCA1, BRCA2 and ATM predicts breast cancer susceptibility. Hum Mol Genet; 16: 1051-1057. Jordheim LP and Dumontet C (2007). Review of recent studies on resistance to cytotoxic deoxynucleoside analogues. Biochim Biophys Acta 1776:138-59

Karchin R, Monteiro AN, Tavtigian SV, Carvalho MA, Sali A (2007). Functional impact of missense variants in BRCA1 predicted by supervised learning. PLoS Comput Biol; 3: e26. Kato I, Canzian F, Plummer M, Franceschi S, van Doorn LJ, Vivas J, Lopez G, Lu Y, GioiaPatricola L, Severson RK, Schwartz AG, Munoz N (2007). Polymorphisms in genes related to bacterial lipopolysaccharide/peptidoglycan signaling and gastric precancerous lesions in a population at high risk for gastric cancer. Dig Dis Sci; 52: 254-261. Kato I, Canzian F, Franceschi S, Plummer M, van Doorn LJ, Lu Y, Gioia-Patricola L, Vivas J, Lopez G, Severson RK, Schwartz AG, Munoz N (2006). Genetic polymorphisms in anti-inflammatory cytokine signaling and the prevalence of gastric precancerous lesions in Venezuela. Cancer Causes Control; 17: 1183-1191. Kato I, van Doorn LJ, Canzian F, Plummer M, Franceschi S, Vivas J, Lopez G, Lu Y, GioiaPatricola L, Severson RK, Schwartz AG, Munoz N (2006). Host-bacterial interaction in the development of gastric precancerous lesions in a high risk population for gastric cancer in Venezuela. Int J Cancer; 119: 1666-1671. Lovelock PK, Healey S, Au W, Sum EY, Tesoriero A, Wong EM, Hinson S, Brinkworth R, Bekessy A, Diez O, Izatt L, Solomon E, Jenkins M, Renard H, Hopper J, Waring P, Tavtigian SV, Goldgar D, Lindeman GJ, Visvader JE, Couch FJ, Henderson BR, Southey M, Chenevix-Trench G, Spurdle AB, Brown MA (2006). Genetic, functional, and histopathological evaluation of two C-terminal BRCA1 missense variants. J Med Genet; 43: 74-83. Lovelock PK, Wong EM, Sprung CN, Marsh A, Hobson K, French JD, Southey M, Sculley T, Pandeya N, Brown MA, Chenevix-Trench G, Spurdle AB, McKay MJ (2006). Prediction of BRCA1 and BRCA2 mutation status using post-irradiation assays of lymphoblastoid cell lines is compromised by inter-cell-line phenotypic variability. Breast Cancer Res Treat; [Epub ahead of print]. Mann GJ, Thorne H, Balleine RL, Butow PN, Clarke CL, Edkins E, Evans GM, Fereday S, Haan E, Gattas M, Giles GG, Goldblatt J, Hopper JL, Kirk J, Leary JA, Lindeman G, Niedermayr E, Phillips KA, Picken S, Pupo GM, Saunders C, Scott CL, Spurdle AB, Suthers G, Tucker K, Chenevix-Trench G (2006). Analysis of cancer risk and BRCA1 and BRCA2 mutation prevalence in the kConFab familial breast cancer resource. Breast Cancer Res; 8: R12. Mathe E, Olivier M, Kato S, Ishioka C, Hainaut P, Tavtigian SV (2006). Computational approaches for predicting the biological effect of p53 missense mutations: a comparison of three 77

Genetics and Epidemiology Cluster sequence analysis based methods. Nucleic Acids Res; 34: 1317-1325. McGuire V, John EM, Felberg A, Haile RW, Boyd NF, Thomas DC, Jenkins MA, Milne RL, Daly MB, Ward J, Terry MB, Andrulis IL, Knight JA, Godwin AK, Giles GG, Southey M, West DW, Hopper JL, Whittemore AS (2006). No increased risk of breast cancer associated with alcohol consumption among carriers of BRCA1 and BRCA2 mutations ages G (V2424G) mutation by gene expression profiling. Genes Chromosomes Cancer; 45: 1169-1181. Voegele C, Tavtigian SV, de Silva D, Cuber S, Thomas A and Le Calvez-Kelm F (2007). A laboratory Information Management System (LIMS) for high throughput genetic platform aimed at candidate gene mutation screening. Bioinformatics, 23(18):2504-6. Ware MD, DeSilva D, Sinilnikova OM, Stoppa-Lyonnet D, Tavtigian SV, Mazoyer S (2006). Does nonsense-mediated mRNA decay explain the ovarian cancer cluster region of the BRCA2 gene? Oncogene ; 25: 323-328.

Pathogenesis and Prevention Cluster (PPC) Cluster Coordinator: Dr Hiroko Ohgaki The Pathogenesis and Prevention Cluster (PPC) comprises four Groups: the Pathology Group (PAT), the Screening Group (SCR), the Screening Quality Control Group (ECN) and the Gambia Hepatitis Intervention Study Group. The ‘pathogenesis’ aspect of the PPC cluster is performed by the Pathology Group. It focuses on the molecular pathology of human neoplasms in particular brain tumours and prostate cancer, with the objectives of correlating histologically recognized phenotypes with genotypes, elucidating the molecular basis and genetic pathways of human tumours, and identifying genetic factors that are predictive of tumour progression. The Pathology Group is also responsible for the production of the 4th edition of the WHO Classification of Tumours Series (WHO Blue Books),

which aims to establish a pathological classification and grading of human tumours that is accepted and used worldwide. Without clearly defined clinical and histopathological diagnostic criteria, and more recently genetic and expression profiles, epidemiological studies and clinical trials are difficult to conduct. The 4th edition of this series was initiated in 2006, and the first volume, Tumours of the Central Nervous System, was published in June 2007. The ‘prevention’ aspect of the PPC cluster is performed by the three other Groups, with emphasis on both lowresource countries and on high- and medium-resource countries. The Screening Group carries out large-scale trials to evaluate various screening and early detection methods for cancers of the uterine cervix, oral cavity and breast, with

the objective of providing data on the accuracy, reproducibility, safety, acceptability, efficacy and cost-effectiveness of different screening interventions in reducing disease burden and in improving quality of life, particularly in low-resource countries. The objective of the Screening Quality Control Group is to expand and strengthen the scientific basis for quality assurance in cancer screening with an initial emphasis on Europe, through the coordination and promotion of international collaboration in the development and implementation of quality assurance guidelines. The Gambia Hepatitis Intervention Study Group supports an ongoing study to assess the effectiveness of vaccination against hepatitis B virus in the prevention of chronic hepatitis B virus infection and hepatocellular carcinoma in the Gambia.

Consensus and Editorial Meeting. WHO Classification of Tumours of the Nervous System. German Cancer Research Centre, Heidelberg 17-18 November, 2006 79

Pathology Group (PAT) Head Dr Hiroko Ohgaki Scientists Dr Lars Egevad (from July 2006) Dr Hervé Huang (until January 2006) Dr Wei-Min Tong (until June 2007) Technical assistants Mrs Anne-Marie Camus-Randon Mrs Nicole Lyandrat (Histology laboratory) The Pathology Group studies the molecular basis of human neoplasms, in particular brain tumours and prostate cancer, using samples of tumours from patients with excellent clinical data and follow-up. The main objectives of the Group are to correlate histologically recognised phenotypes with genotypes and expression profiles, to elucidate the molecular basis and genetic pathways that are operative in human tumorigenesis, to identify those genetic factors that can prognosticate tumour progression and patient outcome and those that are predictive of sensitivity to treatment, and to use genetic data to identify the etiology of human cancers. Since 2006, the Pathology Group has also been responsible for the 4th edition of World Health Organization (WHO) Classification of Tumours Series (WHO Blue Books). The first volume, Tumours of the Central Nervous System, was published in 2007, and the second volume (Tumours of the Haematopoietic and Lymphoid Tissues) is in the editing stages. Molecular pathology of human neoplasms Glioblastomas are histologically and genetically heterogeneous. We have investigated to what extent histological features reflect the genetic profile and whether they are predictive of clinical outcome. Key histological characteristics, 80

Secretariat/database Mr Sébastien Antoni Mrs Pascale Collard

Dr Takuya Watanabe (from March 2007) Dr Izabela Zawlik (from July 2006)

Visiting scientists and postdoctoral fellows Dr Taku Homma (until March 2006) Dr Jian Huang (from June 2006) Dr Daisuke Kita (until March 2007) Dr Shengqing LV (from November 2007) Dr Xiuju Sun (until March 2007)

Student Mr Wen-Hui Cao (until March 2006)

which included major cell types (small cell, non-small cell), other elements such as oligodendroglial components, gemistocytes, multinucleated giant cells, necrosis and microvascular proliferation, of 420 cases of glioblastoma within a populationbased study were re-assessed and correlated with the patients' clinical outcomes and key genetic alterations. Epidermal growth factor receptor (EGFR) amplification and p16INK4a homozygous deletion were significantly more frequent in small-cell glioblastomas than in non-small-cell glioblastomas. Multivariate analyses adjusted for age and gender showed that small-cell glioblastomas had frequent EGFR amplification and p16INK4a deletion but infrequent PTEN mutations. An oligodendroglial component was detected in 20% of glioblastomas; these patients were significantly younger and survived longer. However, multivariate analyses with adjustment for age and gender did not show that the presence of an oligodendroglial component was predictive of longer survival. After adjustment for age and gender, loss of heterozygosity (LOH) 1p was associated with longer survival, whereas LOH 10q was associated with shorter survival of patients with glioblastoma. Glioblastomas that contained >5% multinucleated giant cells showed more frequent TP53 mutation and infrequent EGFR amplification than those

that contained 80%) were located within or near the cerebellum (83%). Histologically, there were 2 major histological types: malignant gliomas and oligodendrogliomas. This is the first transgenic rat model to develop brain tumours. Because v-erbB is structurally and functionally similar to the truncated form of EGFR that is amplified and overexpressed in human glioblastomas,

Pathology Group

S100beta-v-erbB transgenic rats may serve as a useful animal model for the identification of EGFR-related molecular targets and as a tool for the assessment of novel therapeutic approaches. Prostate cancer is now the most commonly diagnosed malignant tumour among men in Western Europe and North America. Prediction of prognosis of prostate cancer in practical health care is today almost entirely limited to traditional clinical and histopathological parameters. The main prognostic indicator, the Gleason grading, has recently undergone revision at a consensus meeting organized by the International Society of Urological

Pathology. We have investigated the reproducibility and clinical use of this modified Gleason score in a series of studies, and found good interobserver reproducibility, a high degree of agreement between biopsies and radical prostatectomy specimens and a good correlation with pathological stage. To identify new prognostic biomarkers of prostate cancer that are detectable by immunohistochemistry, we constructed in collaboration with the Karolinska Institute tissue microarrays from a consecutive series of radical prostatectomy specimens collected in 1998–2002 with clinical follow-up. In addition, we have established

tissue microarrays that contain lymph node metastases and normal anatomical zones of the prostate and others that contain normal peripheral zone, hyperplastic transition zone, high-grade prostatic intraepithelial neoplasia (PIN), cancer and atrophy from the same cases for studies of pathogenesis. We performed immunohistochemical staining for selected biomarkers from previous studies of proteomics (regulators in the redox system, stress-related proteins and others). Among these, the best predictors of outcome after prostatectomy were heat-shock proteins 27 and 60. A collaboration has been established with the Swedish Human Proteome Resource (HPR) project, a large-scale Swedish project endorsed by the Human Proteome Organisation (HUPO) with the purpose of systematically exploring the entire human proteome with antibodybased proteomics. Using high-throughput cloning and expression of Protein Epitope Signature Tags (PrESTs), affinity-purified polyclonal antibodies are produced. The antibodies are validated on protein arrays and western blots, then used for immunohistochemistry on a set of tissue microarray samples that include normal tissue, tumours and cell lines from all major organs of the human body. The results are made public at www.proteinatlas.org. PAT coordinates the HPR’s clinical network for prostate cancer, which allows access to all novel antibodies of the HPR project before publication. We will investigate potential biomarkers from the HPR project and cross-validate them between the network groups. DNA damage response plays an important role in the development of disease and cancer. Poly(ADP-ribose) polymerase-1 (PARP-1) facilitates one of the early DNA repair signalling responses to DNA single-strand breaks. We have observed that PARP-1 deficiency causes the formation of mammary carcinoma in mice after a long latency. Using primary cultured mammary epithelial cells, we found that PARP-1 deficiency results in centrosome amplification, chromosomal aberrations and compromised p53 function, which may represent early molecular and cytogenetic events that lead to malignant transformation. Notably, the 81

Pathogenesis and Prevention Cluster

introduction of p53 heterozygosity into PARP-1 mutant females accelerates mammary carcinogenesis, and p53-null mutation significantly increased the PARP-1 deficiency-induced malignant transformation of mammary epithelial cells at a young age. These results demonstrate that PARP-1 deficiencyinduced centrosome amplification and chromosomal instability trigger genetic alterations, including loss of p53 wild-type allele in mammary epithelium, that contribute to tumour formation. To investigate whether the mutations and alterations of PARP-1 protein levels or activity may be involved in human cancers, we screened for all PARP-1 exons, 7.1-kb of intron-exon junction and 1.0-kb promoter sequences in 83 French patients who had breast cancer and 100 controls by direct sequencing of genomic DNA. Twenty rare genetic variants of PARP-1 were detected in 9 (11%) of the observed breast cancers. We also demonstrated that a common single nucleotide polymorphism (SNP) at codon 762, which results in the substitution of alanine for valine in the catalytic domain of PARP-1 protein, reduces enzymatic activity, suggesting an impact of altered PARP-1 activity in human cancers. In collaboration with Dr Miwa, University of Tsukuba, Japan, we have shown that levels of poly(ADP-ribosyl)ation in vivo are important for the maintenance of correct centrosome duplication and chromosomal stability. We also identified a novel function of the DNA repair molecule Nbs1 in terminal differentiation of the lens fibre cells, and found that Nbs1 deficiency causes an early onset of cataractogenesis. WHO Classification of Tumours Series (WHO Blue Books) The aim of the WHO Classification of Tumours Series (WHO Blue Books) is to establish a pathological classification and

82

grading system for human tumours that is accepted and used worldwide. The 3rd edition was published by IARC in 2005, and covered all organ sites in 10 volumes. In contrast to the 1st and 2nd editions, the 3rd edition covered not only pathology, but also contained concise sections on epidemiology, clinical signs and symptoms, major genetic alterations and expression profiles, and predictive factors. Diagnostic criteria, pathological features and associated genetic alterations were described in a strictly disease-oriented manner. For each volume, 10 000–35 000 copies were printed and distributed worldwide. After the completion of 10 volumes of the 3rd edition, IARC organized a Working Group in December 2005 to review the strengths and weaknesses of that edition and to discuss priority issues for the 4th edition. Series Editors were appointed in early 2006. The major roles of series editors are to select volume editors and to ensure that the pathology and genetics sections are of high quality and consistency throughout the 4th edition. The Series Editors of the 4th edition are Dr Fred Bosman, Institute of Pathology, University of Lausanne, Switzerland (Digestive System Tumours), Dr Elaine Jaffe, National Institutes of Health, Department of Health and Human Services, Bethesda, USA (Hematopathology), Dr Sunil Lakhani, Molecular and Cellular Pathology, University of Queensland Mayne Medical School, Herston, Australia (Breast Cancer), and Dr Hiroko Ohgaki, IARC (Nervous System Tumours). The first volume of the 4th edition is Tumours of the Nervous System. Volume Editors were assigned in April 2006. They are Dr David N. Louis (Harvard Medical School, Boston, USA), Dr Hiroko Ohgaki (IARC), Dr Otmar D. Wiestler (German Cancer Research Center, Heidelberg,

Germany) and Dr Webster K. Cavenee (Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, USA). In June 2006, Volume Editors invited approximately 70 participants from 19 countries to revise 66 different histological types of brain tumours (including approximately 10 new disease entities). The consensus and editorial meeting was held on 17-18 November 2006 in Heidelberg, Germany, to reach consensus for the new disease entities and controversial issues, and to finalize manuscripts. The manuscripts were further edited by the Volume Editors, and layout work was carried out by the Pathology Group. This volume was published in June 2007. The second volume is Tumours of the Haematopoietic and Lymphoid Tissues (3rd edition published in July 2001). Volume Editors were selected in September 2006. They are Dr S.H. Swerdlow (UPMC Presbyterian, Pittsburgh, USA), Dr E. Campo (Hospital Clinic, University of Barcelona, Spain), Dr N.L. Harris (Massachusetts General Hospital, Boston, USA), Dr E. Jaffe (National Institutes of Health, Department of Health and Human Services, Bethesda, USA), Dr S. Pileri (Institute of Haematopathology and Clinical Oncology, St Orsola-Malpighi Hospital, University of Bologna, Italy), Dr H. Stein (Institute of Pathology, Klinikum Benjamin Franklin, Berlin, Germany), Dr J. Thiele (Institute of Pathology, University of Cologne, Germany) and Dr J. Vardiman (University of Chicago Medical Center, Chicago, USA). Approximately 140 contributors from 24 countries were invited in March 2007. A consensus and editorial meeting took place at IARC in October 2007, and the volume is scheduled to be published in the first half of 2008.

Pathology Group

The Pathology Group is grateful to the following scientists for their collaboration in our projects: Dr F. Bosman, Geneva, Switzerland; Dr D.J. Brat, Atlanta, USA; Dr E. Campo, Barcelona, Spain; Dr W.K. Cavenee, La Jolla, USA; Dr L. Frappart, Lyon, France; Dr F. Giangaspero, Rome, Italy; Dr N.L. Harris, Boston, USA Dr F. Heppner, Zurich, Switzerland; Dr E. Jaffe, Bethesda, USA; Dr P. Kleihues, Zurich, Switzerland; Dr S.R. Lakhani, Herston, Australia; Dr D.N. Louis, Boston, USA; Dr M. Miwa, Tsukuba, Japan; Dr Y. Nakazato, Gunma, Japan Dr A. Perry, St Louis, USA; Dr S. Pileri, Bologna, Italy; Dr N. Probst, Zurich, Switzerland; Dr Y. Shen, Beijing, People’s Republic of China; Dr H. Stein, Berlin, Germany; Dr S. Swerdlow, Pittsburgh, USA Dr J. Thiele, Cologne, Germany; Dr J. Vardiman, Chicago, USA; Dr W.A. Weiss, San Francisco, USA Dr S. Wellek, Mannheim, Germany; Dr M. Weller, Tubingen, Germany; Dr O.D. Wiestler, Heidelberg, Germany; Dr Y. Yonekawa, Zurich, Switzerland

The financial support from the following bodies is gratefully acknowledged: Foundation for Promotion of Cancer Research, Japan Comité Départemental de la Drôme, la Ligue Nationale Contre le Cancer, France Comité Départemental de la Loire, la Ligue Nationale Contre le Cancer, France Chinese National Genome Center, Beijing, China Maud and Birger Gustavsson Foundation, Sweden

Publications Original papers Allen NE, Key TJ, Appleby PN, Travis RC, Roddam AW, Rinaldi S, Egevad L, Rohrmann S, Linseisen J, Pischon T, Boeing H, Johnsen NF, Tjonneland A, Gronbaek H, Overvad K, Kiemeney L, Bueno-de-Mesquita HB, Bingham S, Khaw KT, Tumino R, Berrino F, Mattiello A, Sacerdote C, Palli D, Quiros JR, Ardanaz E, Navarro C, Larranaga N, Gonzalez C, Sanchez MJ, Trichopoulou A, Travezea C, Trichopoulos D, Jenab M, Ferrari P, Riboli E and Kaaks R (2007). Serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 concentrations and prostate cancer risk: results from the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiol Biomark Prev; 16:1121-1127. Brat DJ, Shehata BM, Castellano-Sanchez AA, Hawkins C, Yost RB, Greco C, Mazewski C, Janss A, Ohgaki H and Perry A (2007). Congenital glioblastoma: A clinicopathologic and genetic analysis. Brain Pathol; in press. Cao WH, Wang X, Frappart L, Rigal D, Wang ZQ, Shen Y and Tong W-M (2007). Genetic variants analysis of poly(ADP-ribose) polymerase-1 gene in breast cancer in French patients. Mutat Res; in press.

Egevad L, Håkansson U, Ehrnström R and Grabe M (2007). Primary seminal vesicle carcinoma diagnosed at transurethral resection of the prostate. Urology Apr; 69: 778.e11-3. Fukushima T, Favereaux A, Huang H, Shimizu T, Yonekawa Y, Nakazato Y and Ohgaki H (2006). Genetic alterations in primary glioblastomas in Japan. J Neuropathol Exp Neurol; 65: 12-18. Giangaspero F, Wellek S, Masuoka Gessi JM, Kleihues P and Ohgaki H (2006). Stratification of medulloblastoma on the basis of histopathological grading. Acta Neuropathol; 112: 5-12. Helpap B and Egevad L (2006). The Significance of Modified Gleason Grading of Prostatic Carcinoma in Core Biopsies and Radical Prostatectomy Specimens Virchows Arch; 449: 622-627. Helpap B and Egevad L (2007). The value of the modified Gleason grading system of prostate adenocarcinoma in routine urological diagnostics. Urologe A Jan; 46(1): 59-62. Homma T, Fukushima T, Vaccarella S, Yonekawa Y, Di Patre PL, Franceschi S and Ohgaki H (2006). Correlation among pathology, genotype and patient outcomes in glioblastoma. J Neuropathol Exp Neurol; 65: 846-854.

Kanai M, Tong WM, Wang ZQ, Miwa M (2007). Haploinsufficiency of poly(ADPribose) polymerase-1-mediated poly(ADPribosyl)ation for centrosome duplication. Biochem Biophys Res Commun 359: 426-430. Key TJ, Appleby PN, Allen NE, Travis RC, Roddam AW, Jenab M, Egevad L, Tjønneland A, Johnsen NF, Overvad K, Linseisen J, Rohrmann S, Boeing H, Pischon T, Psaltopoulou T, Trichopoulou A, Trichopoulos D, Palli D, Vineis P, Tumino R, Berrino F, Kiemeney L, Bueno-de-Mesquita HB, Quirós JR, González C, Martinez C, Larrañaga N, Chirlaque MD, Ardanaz E, Stattin P, Hallmans G, Khaw K-T, Bingham S, Slimani N, Ferrari P, Rinaldi S and Riboli E (2007). A prospective study of plasma carotenoids, retinol, tocopherols and prostate cancer risk. Am J Clin Nutr; in press. Kita D, Yonekawa Y, Weller M and Ohgaki H (2007). PI3KCA alterations in primary (de novo) and secondary glioblastomas. Acta Neuropathol; 113: 295-302. Naumann U, Huang H, Wolburg H, Wischhusen J, Weit S, Ohgaki H and Weller M (2006). PCTAIRE3: a putative mediator of growth arrest and death induced by CTS-1, a dominant-positive p53-derived synthetic tumor suppressor, in human malignant glioma cells. Cancer Gene Therapy; 13: 469-478.

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Pathogenesis and Prevention Cluster Ohgaki H, Kita D, Favereaux A, Huang H, Homma T, Dessen P, Weiss WA, Kleihues P and Heppner FL (2006). Brain tumors in S100beta-v-erbB transgenic rats. J Neuropathol Exp Neurol; 65: 1111-1117. Soldan K, Pooley FD, Hansen J, Andersen A, Chang-Claude J, Ferro G, Ohgaki H, Skov BG, Cherrie JW, Saracci R and Boffetta P (2006). Lung fibre burden in lung cancer cases employed in the rock and slag wool industry. Ann Occup Hyg; 50: 241-248. Tazawa H, Tatemichi M, Sawa T, Gilibert I, Ma N, Hiraku Y, Donehower LA, Ohgaki H, Kawanishi S and Ohshima H (2007). Oxidative and nitrative stress caused by subcutaneous implantation of a foreign body accelerates sarcoma development in Trp53+/- mice. Carcinogenesis; 28: 191-198.

invasiveness in human malignant gliomas cells. Cell Death Differ; 13: 1156-1169. Yang YG, Frappart PO, Frappart L, Wang ZQ and Tong W-M (2006). A novel function of DNA repair molecule Nbs1 in differentiation of the lens fibre cells and cataractogenesis. DNA Repair; 5: 885-893. Yin L, Puliti A, Bonora E, Evangelisti C, Conti V, Tong W-M, Medard JJ, Lavoue MF, Forey N, Wang LC, Manie S, Morel G, Raccurt M, Wang ZQ and Romeo G (2007). C620R mutation of the murine ret proto-oncogene: Loss of function effect in homozygotes and possible gain of function effect in heterozygotes. Int J Cancer; 121: 292-300.

Reviews

Tong W-M, Lee MK, Galendo D, Wang ZQ and Sabapathy K (2006). Aslatoxin B1 exposure does not lead to p53 mutation but results in enhanced hepatocelluar carcinoma formation in Hupki (human p53 knock in) mice. Int J Cancer; 119: 745-749.

Ohgaki H and Kleihues P (2007). Review: Genetic pathways to primary and secondary glioblastoma. Am J Pathol; 170(5): 1445-1453.

Tong W-M, Yang YG, Cao WH, Galendo D, Frappart L, Shen Y and Wang ZQ (2007). Poly(ADP-ribose) polymerase-1 plays a role in suppressing mammary tumorigenesis in mice. Oncogene; 26: 3857-3867.

Kleihues P, Burger PC, Aldape KD, Brat DJ, Bigner DD, Nakazato Y, Plate KH, Giangaspero F, von Deimling A, Ohgaki H and Cavenee WK (2007). Glioblastoma. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds.) WHO Classification of the Central Nervous System, Lyon: IARC; 33-49.

Wang XG, Wang ZQ, Tong W-M and Shen Y (2007). PARP1 Val762Ala polymorphism reduces enzymatic activity. Biochem Biophys Res Commun; 354: 122-126. Weiler M, Bahr O, Hohlweg U, Naumann U, Rieger J, Huang H, Tabatabai G, Krell HW, Ohgaki H, Weller M and Wick W (2006). BCL-X(L): time-dependent dissociation between modulation of apoptosis and

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Book chapters

Kleihues P, Chimelli L, Giangaspero F and Ohgaki H (2007). Cerebellar liponeurocytoma. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds.) WHO Classification of the Central Nervous System, Lyon: IARC; 110112.

Minniti G, Brada M, Kleihues P and Ohgaki H (2006). Gliomas. In: Gospodarowicz MK, O’Sullivan B, Sobin LH (eds.) Prognostic Factors in Cancer, UICC Prognostic Factors in Cancer, 3rd Edition, John Wiley & Sons; 307312. Ohgaki H, Olivier M and Hainaut P (2007). Li-Fraumeni syndrome and TP53 germline mutations. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds.) WHO Classification of the Central Nervous system, Lyon: IARC; 222-225. von Deimling A, Burger PC, Nakazato Y, Ohgaki H and Kleihues P (2007). Diffuse astrocytoma. In: Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (eds.) WHO Classification of the Central Nervous System, Lyon: IARC; 25-29.

Book Louis DN, Ohgaki H, Wiestler OD, Cavenee W (eds.) (2007). WHO Classification of Tumours of the Central Nervous System, Lyon: IARC.

Screening Group (SCR) Head Dr Rengaswamy Sankaranarayanan Scientist Dr Catherine Sauvaget (from July 2006) Technical assistants Ms Silvina Arrossi (until mid-January 2007) Mr Jean-Marie Fayette Ms Krittika Guinot Mr Eric Lucas Mr Richard Muwonge (from June 2006) Programme assistant Ms Evelyn Bayle

Secretaries Ms Odile Bouvy Ms Mary Renaud (from February 2006) Visiting scientists Ms Rhian Gabe January 2006 Dr René Lambert January 2006-November 2008 Dr Rajaraman Swaminathan mid January-December 2006 Dr Ramadas Kunnambath July 2007-July 2008 Dr M. Siddiqi December 2007-March 2008

Ms Delphine Boca April-mid July 2006 Mr Guillaume Martin mid June-July 2006 Mr Guillaume Vitti mid May-July 2006 Dr Pattarawin Attasara April-May 2007 Ms Marianna De Camargo Cancella April-September 2007 Ms Michèle Dumont-Portugais April-June 2007 Mr Arthur Munoz mid May-mid June 2007 Mr Guillaume Vialaneix mid May-mid June 2007

Students Mr Yann Bachelard mid June-July 2006 The objective of Screening Group projects is to guide the development of evidencebased public health policies in implementing cancer screening and early diagnosis in a range of health care settings, particularly in low- and medium-resource countries, leading to rational utilisation of health care resources and improving quality of life. To meet this requirement, our studies address the accuracy, reproducibility, efficacy, benefits, harmful effects and cost-effectiveness of different screening interventions for breast, cervical, oral and other cancers and development of quality assurance standards for screening in different settings, in collaboration with national institutions in different countries. Cervical cancer screening studies The efficacy of a once-in-a-lifetime screening using cervical cytology or HPV testing or visual inspection with acetic acid (VIA) in preventing cervical cancer cases and deaths is being assessed in two clusterrandomised controlled trials involving 210 000 women aged 30–59 years in India. In both the trials, screen-positive women had colposcopy and directed biopsies, and

women with CIN were treated with cryotherapy by nurses or loop excision by doctors. Screening was carried out during 2000–2003, and the study cohorts are followed up for cervical cancer incidence and mortality in both studies. We have now updated results for 7 years of followup after screening commenced and have reported results in terms of incidence and mortality reduction in one study. In the Dindigul District Screening trial, 57 study clusters were randomised to a single round of VIA by trained nurses, and 57 to a control group. The outcome in terms of cervical cancer incidence and mortality has been analysed and the results published in The Lancet. Of the 49 311 eligible women aged 30–59 years in the VIA group, 31 343 (63.6%) were screened during 2000–2003; 30 958 women in the control group received routine care. Of the 1874 women with precancerous lesions in the intervention group, 72% received treatment. During 2000–2006, there were 167 cervical cancer cases and 83 cervical cancer deaths in the intervention group, compared with 158 cases and 92 deaths and in the control group, yielding an

incidence hazard ratio of 0.75 (95% CI 0.55-0.95) and mortality hazard ratio of 0.65 (95% CI 0.47-0.89). The greatest reduction in incidence and mortality rates was observed for the 30–39 year age group. The reductions in cervical cancer incidence (hazard ratio 0.62 [95% CI: 0.40-0.96]) and mortality (hazard ratio 0.34 [95% CI: 0.18-0.66]) were greatest in the 30–39 year age group. There were 1303 total deaths in the intervention group and 977 deaths in the control group yielding agestandardised all-cause death rates of 585.7 and 619.4 per 100 000, respectively, a significant 13% reduction in all-cause mortality (hazard ratio 0.87 [95% CI: 0.78-0.96]) in the intervention group, possibly due to the augmented health care opportunities offered by the screening intervention and due to the reduction in cervical cancer deaths, since cervical cancer is the leading cause of death in this population, accounting for 11% of all deaths in women aged 30–59 years. We have now commenced providing a single round of screening for the control group women, as part of our ethical obligation.

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Pathogenesis and Prevention Cluster

In the Osmanabad district a clusterrandomised controlled trial is investigating the efficacy and cost-effectiveness of a single round of screening by VIA (34 000 women), cytology (32 000 women) or HPV testing (34 000 women) as compared to a control group (31 400 women) receiving routine care plus health education on cervical cancer prevention in incidence and mortality. The screening rounds were completed during 2000–2003. More than 70% of the women in the different groups were screened. The detection rate of high-grade lesions was similar in all intervention arms: 0.7% for VIA, 1.0% for cytology and 0.9% for HPV testing. During 2000–2006, there were 110 invasive cancer cases in the HPV group, 138 in the cytology group, 137 in the VIA group and 74 cases in the control group. More than half of the invasive cancer cases in the screened groups had stage I disease as compared to a fifth of those in the unscreened control group. There were 19 cervical cancer deaths in the HPV group, 38 deaths in the cytology group, 37 deaths in the VIA group and 29 deaths in the control group. There seems to be considerable underdiagnosis and underregistration of invasive cervical cancer cases and deaths in the control group due to poorly developed cancer services in the district, and thus the cervical cancer incidence rates have not caught up with the rates in the intervention groups so far. Even with these limitations, as of now there is a significant reduction in the incidence of advanced cancers (RR: 0.58) in the HPV group as compared to the

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control group. With cytology as the reference group, both cervical cancer incidence (RR: 0.76) and mortality (RR: 0.49) are significantly lower in the HPV group; incidence and mortality rates are similar in both cytology and VIA groups. The ultimate effectiveness of the 3 approaches will become clear with followup for cancer incidence and mortality. Factors influencing participation in screening and treatment in this study have been addressed and results published. We have analysed and reported the effectiveness of field-based cryotherapy and loop excision treatment for CIN based on the cases treated in the Dindigul and Osmanabad screening trials.The cure rates exceed 90% for CIN and are similar to results obtained in hospital-based care in developed countries. Minor side effects and complications were reported in less than 10% of women and these treatments are judged to be effective, safe and acceptable to women. The Screening Technologies to Advance Rapid Testing (START) project for Cervical Cancer Prevention aims to develop, evaluate and make available affordable and accurate biochemical tests for the early detection of CIN in public health and clinical practice in developing countries. Field activities of the START project have been underway since September 2005 in Solapur district, India, in collaboration with the Nargis Dutt Memorial Cancer Hospital (NDMCH), Barshi and the Tata Memorial Centre (TMC), Mumbai, contributing to the development, validation and future commercial availability of the new test formats. As of April 2007, we have screened 8973 women and collected 35 900 cervical and vaginal samples for test development and validation. Currently the fast HPV test, which will yield results within 3 hours, and a strip test for detecting E6 antigen are undergoing validation. Seven training courses in cervical cancer screening and prevention were conducted and around 100 doctors and nurses from 12 Asian countries were trained:

Beijing, China Course on Cervical Cancer Screening Methods and Treatment with Loop Electrosurgical Excision Procedure (28-30 April 2006)

Ambilikkai, India Cervical Cancer Screening Methods and Treatment of Lesions with Large Loop Electrosurgical Excision Procedure (1-3 January 2006)

Oral cancer screening Following a 34% reduction in oral cancer mortality among users of tobacco or alcohol or both observed in a randomised controlled screening trial involving

Bangkok, Thailand Course on Early Detection and Prevention of Cervical Cancer (22-25 May 2006) Port Vila, Vanuatu Course on Cervical Screening using VIA and VILI and Treatment of Cervical Neoplasia using Cryotherapy (15-19 January 2007) Barshi, India Course on Early Detection and Prevention of Cervical Cancer and Screening Programme Implementation (6-9 June 2007) Chiang Rai, Thailand Colposcopy on Cervical Cancer Screening and Treatment of CIN (12-14 June 2007) Ambilikkai, India Early Detection, Prevention and Treatment of Cervical Pre-Cancers 14-17 November 2007) We also published digital training manuals for cervical screening and treatment of CIN. We have submitted a letter of inquiry (LOI) to the Bill & Melinda Gates Foundation seeking funding to support a major randomised clinical trial in collaboration with TMC, NDMCH and CFCHC in India to generate scientific evidence on the clinical efficacy of twodose HPV vaccination as compared with the current standard three-dose vaccination to prevent persistent HPV infection and cervical neoplasia in order to guide public health policies for planning and implementing wide-scale, sustained HPV vaccination delivery to pre- and early adolescent girls. This study will involve around 16 000 girls aged 10–18 years.

Screening Group

200 000 subjects in Trivandrum district, Kerala, India, we have now completed providing a single round of oral screening for the 100 000 control subjects, as part of our ethical obligation. Continuing followup of the study cohorts for oral cancer mortality is progressing well. The cost effectiveness of oral cancer screening is now being addressed in this study. The natural history of oral precancerous lesions such as leukoplakia and submucous fibrosis in terms of probabilities of regression, persistence, and progression to invasive cancer is being studied. The factors influencing participation in screening have been analysed. The overall and cause-specific mortality experience of participants in this study are currently

being analysed to establish the risk levels and patterns of death associated with various types of tobacco and alcohol drinking habits as well as body weight patterns prevailing in the region.

outcome of breast cancer. This study has recruited around 80 000 women as of June 2007. A clinical reference chart to help in the early diagnosis of breast cancer has been developed and will be validated.

Breast cancer screening A cluster-randomised controlled trial involving 120 000 women in Kerala, India was initiated in 2006 in collaboration with the Regional Cancer Centre (RCC), Trivandrum, India, to evaluate the effectiveness of a comprehensive intervention consisting of health education, opportunities for clinical early diagnosis and the provision of readily accessible diagnosis and treatment services in the clinical early detection and improved

Other studies We have submitted proposals for funding studies that will address screening for cervix, oral and breast cancers at the same time, combining clinical breast examination, VIA and oral visual inspection, and will evaluate their impact on disease burden in routine health care settings, in order to catalyse wider implementation of screening in lowresource countries and regions.

The SCR Group is grateful to the following for their collaboration in the projects: Dr Adelaide de Carvalho, National Director of Public Health, Luanda, Angola Dr Miraldina da Ganda Manuel, Maternidade Lucrecia Paim, Luanda, Angola Dr Silvio Tatti, Faculty of Medicine, Buenos Aires, Argentina Dr Silvina Arrossi, CEDES, Buenos Aires, Argentina Dr Marc Arbyn, Scientific Institute of Public Health, Brussels, Belgium Dr Ian Magrath, International Network for Cancer Treatment & Research, Brussels, Belgium Dr Paulo Naud, Dr Jean Matos, Instituto de Prevencao du Cancer de Colo do Utero, Porte Alegre, Brazil Dr L. Santini, INCA, Rio de Janeiro, Brazil Dr Boblewende Sakande, Dr Marius Nacoulma, Centre Hospitalier National Yalgado Ouédraogo, Ouagadougou, Burkina Faso Dr Youlin Qiao, Cancer Institute of the Chinese Academy of Medical Sciences, Beijing, China Dr Yong-Bing Xiang, Shanghai Cancer Institute, Shanghai, China Dr Jiang-Guo Chen, Qidong Liver Cancer Institute, Qidong, China Dr Chen Kexin, Tianjin Cancer Registry, Tianjin, China Dr Chun-Key Law, Mr. Oscar Mang, Hong Kong Cancer Registry Dr Raul Murillo, Dr Carlos Vicente Rada Escobar, Dr Joaquin G. Luna Rios Instituto Nacional de Cancerología, Bogota, Colombia Dr Rolando Herrero, Dr Adolfo Ortiz, Ministry of Health, San Jose, Costa Rica Dr Leticia Fernandez Garrote, Dr Yaima Galan Alvarez, National Institute of Oncology and Radiobiology, Havana, Cuba Dr Lucien Frappart, Hopital Edourard Herriot, Lyon, France Dr Bernard Fontaniere, Centre Leon Berard, Lyon, France Dr Thuy Tien Couty, Hospices Civils de Lyon, Lyon, France Dr Ebrima Bah, Gambia Cancer Registry, Banjul, The Gambia Dr Moussa Koulibaly, Dr Namory Keita, CHU Donka, Conakry, Guinea Dr Ketayun Dinshaw, Dr Surendra Shastri, Dr Roshan Chinoy, Dr Kedhar Deodhar, Dr Rohini Kelkar, Dr Rajesh Dikshit, Tata Memorial Centre, Mumbai, India Dr Bhagwan M. Nene, Mrs Kasturi Jayant, Mr Madan Chauhan, Nargis Dutt Memorial Cancer Hospital, Barshi, India Dr Balakrishnan Rajan, Dr Kunnambathu Ramadas, Dr Ramani Wesley, Dr Thara Somanathan, Regional Cancer Centre, Trivandrum, India Dr V. Shanta, Dr R. Swaminathan, Cancer Institute (WIA), Chennai, India Dr Neerja Bhatla, All India Institute of Medical Sciences, New Delhi, India

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Pathogenesis and Prevention Cluster

Dr Rameshwar Sharma, Dr Nisha Naruka, Bhagwan Mahaveer Cancer Hospital & Research Centre, Jaipur, India Dr Partha Basu, Dr Ranajit Mandal, Chittaranjan National Cancer Institute, Kolkata, India Dr Maqsood Siddiqi, Cancer Foundation of India, Kolkata, India Dr Srabani Mittal, Mr Samiran Das, Saktipada Das Memorial Foundation, Kolkata, India Dr Arun Kurkure, Dr Balakrishna Yeole, Indian Cancer Society, Mumbai, India Dr Mary Cherian, Dr Pulikatil Okkaru Esmy, Christian Fellowship Community Health Centre, Ambillikai, India Dr S. Ramalingam, Dr Thomas Chacko, PSG Institute of Medical Sciences & Research, Coimbatore, India Dr B.V. Bhat, Mr Krishnanandha Pai, Malabar Cancer Care Society, Kannur, India Dr Bela Shah, Dr Kishore Chaudhry, Indian Council of Medical Research, New Delhi, India Dr Abraham Peedicayil, Christian Medical College, Vellore, India Dr P. Usha Rani Reddy, MNJ Cancer Institute, Hyderabad, India Dr Shalini Rajaram, University College of Medical Sciences, New Delhi, India Dr Walter Prendiville, Coombe Women’s Hospital, Dublin Dr Alongkone Phengsavanh, Dr Phouthone Sithideth, Faculty of Medical Sciences, Vientiane, People’s Democratic Republic of Laos Professeur Siné Bayo, Professeur Amadou Dolo, Hôpital Gabriel Touré, Bamako, Mali Dr Aarati Shah, Dr D. Raj Karnikar, Bhakthapur Cancer Care Centre, Bhakthapur, Nepal Dr Murari Man Shrestha, Dr Balman Singh Karki, BP Koirala Memorial Cancer Hospital, Bharathpur, Nepal Dr Surendra Shrestha, Nepal Network of Cancer Treatment & Research, Banepa, Nepal Dr Hassan Nouhou, Faculté des Sciences de la Santé, Université de Niamey, Niamey, Niger; Dr Madi Nayama, Maternité Issaka Gazoby, Niamey, République du Niger. Dr Carlos L. Santos, Dr Carlos Vallejos Sologuren, Instituto Especializado de Enfermedades Neoplasicas, Lima, Peru Dr A.V. Laudico, Philipine Cancer Society, Manila, Philippines Dr Divina B. Esteban, Rizal Medical Center, Pasig City, Metro Manila, Philippines Professeur Charles Gombe Mbalawa, Dr Judith Malanda-Mfinga Université Marien Ngouabi, Brazzaville, Republic of Congo Dr Joseph Kokolo, Brazzaville Cancer Registry, Brazzaville, Republic of Congo Dr Kee-Seng Chia, National University of Singapore, Singapore Dr Swee Chong Quek, KK Women’s & Children’s Hospital, Singapore Dr Hai-Rim Shin, Busan Cancer Registry, National Cancer Center Research Institute, South Korea Dr Myung-Hee Shin, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea Dr Yoon-Ok Ahn, Seoul National University College of Medicine, Seoul, South Korea Dr Twalib A. Ngoma, Ocean Road Cancer Institute (ORCI), Dar es Salaam, Tanzania Dr Thiravud Khuhaprema, Dr Petcharin Srivatanakul, Dr Attasara Pattarawin National Cancer Institute, Bangkok, Thailand Dr Nimit Martin, Dr Surathat Pongnikorn, Lampang Cancer Centre, Lampang, Thailand Dr Hutcha Sriplung, University of Songkhla, Songkhla, Thailand Dr Sultan Eser, Izmir Cancer Registry, Izmir, Turkey Dr Gokhan Tulunay, Dr Serdar Yalvac, Dr Nejat Ozgul, SB Ankara Etlik Maternity and Women’s Health Teaching Research Hospital, Ankara, Turkey Dr Henry Wabinga, Makerere University Medical School, Kampala, Uganda Professor Alastair Gray, Dr Linda Legood, Health Economics Research Centre, University of Oxford, Oxford, UK Professor Stephen W. Duffy, Cancer Research Center for Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, London, UK Dr (Mrs) Sudha Sundar, Cheltenham General Hospital, Gloucestershire Hospitals, NHS Foundation Trust, Gloucester, UK Dr Jackie Sherris, Dr Vivien Tsu, Dr John Sellors, Program for Appropriate Technology in Health, Seattle, USA Dr Paul Blumenthal, Dr Lynne Gaffikin, USA Dr Amy Pollack, EngenderHealth, New York, USA Dr Silvana Luciani, Pan American Health Organisation, Washington, USA Dr Sujha Subramanian, RTI International,Waltham, USA Dr Margaret Borok, Mr Eric Chokunonga, Parirenyatwa Hospital, Harare, Zimbabwe Dr Antonio Filipe Jr, WR, Dakar, Senegal

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Screening Group

Financial support from the following bodies is gratefully acknowledged: The Bill & Melinda Gates Foundation, Seattle, USA Program for Appropriate Technology in Health, Seattle, USA Association for International Cancer Research, St. Andrews, UK International Network for Cancer Treatment & Research, Brussels, Belgium African Regional Office of the World Health Organization, Brazzaville, Congo

Publications Arbyn M, Tulunay G, Ozgul N, Yalvac S, Verguts J, Poppe W, Sankaranarayanan R (2006). European Union support for a Turkish reproductive health project to assess alternative cervical cancer screening methods in Sanliurfa (rural south-east Turkey). Eur J Cancer Prev; 15(6): 552-553.

fluoroscopy: is it safe? Gastrointest Endosc; 65(6): 929-931. Lambert R, Hainaut P (2007). Esophageal cancer: cases and causes (part I). Endoscopy; 39(6): 550-555.

Ramadas K, Arrossi S, Thara S and Sankaranarayanan R (2006). Keynote comment: Importance of recognising scientific evidence. Lancet Oncol; 7(12): 962-963.

Lambert R and Hainaut P (2007). Esophageal cancer: the precursors (part II). Endoscopy; 39(7): 659-664.

Sankaranarayanan R (2006). Preventing cervical cancer in low-resource settings. Indian journal of gynaecologic oncology; 6 (Suppl 1): 13-17.

Arrossi S, Matos E, Zengarini N, Roth B, Sankaranarayanan R, Parkin M (2007). The socio-economic impact of cervical cancer on patients and their families in Argentina, and its influence on radiotherapy compliance. Results from a cross-sectional study. Gynecol Oncol; 105(2): 335-340.

Lambert R, Mahé C (2006). Screening for digestive cancers: from theory to practice. World Gastroenterology News; 11(1): 42-45.

Sankaranarayanan R (2006). Overview of cervical cancer in the developing world. Int J Gynaecol Obstet; 95 (Suppl 1): S205-210.

Lambert R, Kuznetsov K, Rey JF (2007). Narrow-band imaging in digestive endoscopy. Scientific World Journal; 7: 449-465.

Basu P, Sarkar S, Mukherjee S, Ghoshal M, Mittal S, Biswas S, Mandal R, Sankaranarayanan R (2006). Women's perceptions and social barriers determine compliance to cervical screening: Results from a population based study in India. Cancer Detect Prev; 30(4): 369-374.

Lambert R, Plummer M (2007). Stomach cancer: epidemiology, precursor conditions, and detection. World Gastroenterology News; 12: 2125.

Sankaranarayanan R, Dinshaw K, Nene BM, Ramadas K, Esmy PO, Jayant K, Somanathan T and Shastri S (2006). Cervical and oral cancer screening in India. J Med Screen; 13 (Suppl 1): S35-S38.

Bradley J, Coffey P, Arrossi S, Agurto I, Bingham A, Dzuba I, Kleine AM, Lewis R, White SC (2006). Women’s perspectives on cervical screening and treatment in developing countries: experiences with new technologies and service delivery strategies. Women Health; 43(3): 103-121. Denny L and Sankaranarayanan R (2006). Secondary prevention of cervical cancer. Int J Gynaecol Obstet; 94 (Suppl 1): S65-S70. Dikshit RP, Ramadas K, Hashibe M, Thomas G, Somanathan T, Sankaranarayanan R (2006). Association between diabetes mellitus and premalignant oral diseases: A cross sectional study in Kerala, India. Int J Cancer; 118(2): 453-457. Kuznetsov K, Lambert R, Rey JF (2006). Narrow-band imaging: potential and limitations. Endoscopy; 38(1): 76-81. Lambert R (2006). Reply to the letter of Dr Cho et Al. Endoscopy; 38(4): 430. Lambert R (2006). Upper gastrointestinal tumors. Endoscopy; 38(2): 133-136. Lambert R (2007). Insertion of expandable metallic stents in esophageal cancer without

Lambert R, Saito H, Saito Y (2007). Highresolution endoscopy and early gastrointestinal cancer … dawn in the East. Endoscopy; 39(3): 232-237. Muwonge R, Ramadas K, Sankila R, Somanathan T, Thomas G, Vinoda J and Sankaranarayanan R (2007). Role of tobacco smoking, chewing and alcohol drinking in the risk of oral cancer in Trivandrum, India: a nested case-control design using incident cancer cases. Oral Oncol; J. Med Screen; 14(3): 144-150. Muwonge R, Walter SD, Wesley RS, Basu P, Shastri S, Thara S, Gombe-Mbalawa C, Sankaranarayanan R for the IARC Multicentre Study Group on Cervical Cancer Early Detection (2007). Assessing the gain in diagnostic performance when two visual inspection methods are combined for cervical cancer prevention. J Med Screen; J Med Screen 14(3): 144-150. Nene B, Jayant K, Arrossi S, Shastri S, Budukh A, Hingmire S, Muwonge R, Malvi S, Dinshaw K and Sankaranarayanan R (2007). Determinants of women’s participation in cervical cancer screening trial, Maharashtra, India. Bull World Health Organ; 85(4): 264272.

Sankaranarayanan R, Esmy PO, Rajkumar R, Muwonge R, Swaminathan R, Shanthakumari S, Fayette JM, Cherian J (2007). Effect of visual screening on cervical cancer incidence and mortality in Tamil Nadu, India: a clusterrandomised trial. Lancet; 370: 398-406. Sankaranarayanan R, Rajkumar R, Esmy PO, Fayette JM, Shanthakumary S, Frappart L, Thara S, Cherian J (2007). Effectiveness, safety and acceptability of ‘see and treat’ with cryotherapy by nurses in a cervical screening study in India. Br J Cancer; 96(5): 738-743. Sherris J, Wright TC, Denny L, Sankaranarayanan R, Pollack AE, Sanghvi H, Sellors JW (2007). Alliance for cervical cancer prevention: setting the record straight. Am J Public Health; 97(2): 200-201.

Book chapters Arrossi S, Sankaranarayanan R, Parkin M (2006). Incidencia y Mortalidad del cáncer cervicouterino en America Latina. En: Alonso, P, Lazcano-Ponce E, Hernández M. (Editores). Cáncer cervicouterino. Diagnóstico, prevención y control. Segunda Edición. México, Editorial Medica Panamericana; 179-188. Denny L, Quinn M, Sankaranarayanan R (2006). Chapter 8: Screening for cervical cancer in developing countries. Vaccine; 24(Suppl 3): S71-S77. 89

Pathogenesis and Prevention Cluster Sankaranarayanan R, Ferlay J (2006). Worldwide burden of gynaecological cancer: The size of the problem. Best Pract Res Clin Obstet Gynaecol; 20(2): 207-225. Sankaranarayanan R, Ramadas K, Ashrafunnessa M, Aziz Z, Shah A, Somanathan T, Aryaratne M (2006). Screening.

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In: Dinshaw KA, Shastri SS, Kurkure AP, Nandakumar A, (ed). Cancer awareness, prevention and control:strategies for South Asia. UICC Handbook, Geneva; UICC; 135147. Sankaranarayanan R, Thara S and Ngoma T (2006). Visual screening for cervical neoplasia.

In: Jordan J, Singer A, Jones H, Shafi M (eds). The Cervix. Blackwell Publishing, London, 29B: 434-441.

Screening Quality Control Group (ECN)

Head Dr Lawrence von Karsa

Programme Assistant Mrs Marie-Pascale Cottard

Student Mr Driss Ait Ouakrim ( January– August 2007)

Breast, cervical and colorectal cancer currently account for approximately one of four cancer deaths, are a major cause of suffering, and are of significant concern to women and men worldwide. Demographic changes in the world’s population are likely to lead to substantial increases in the burden of breast and colorectal cancer in the future due to the higher incidence of these cancers with increasing age. The recent dramatic rises in the prevalence of human papillomavirus infection in young women commonly attributed to lifestyle changes also suggest that the burden of cervical cancer will increase substantially in coming decades if preventive action is not taken. Fortunately, secondary prevention of these cancers through population-based screening programmes is an effective option for cancer control, provided high quality of the screening process is maintained. Quality assurance of the screening process requires a robust system of programme management and coordination, assuring that all aspects of the service are performing adequately. Attention must be paid not only to communication and technical aspects but also to qualification of personnel, performance monitoring and auditing, as well as evaluation of the impact of screening on the burden of the disease. Population-based screening policy and organisation conforming to evidencebased standards and procedures provide the overall programmatic framework essential to implementation of quality assurance and are therefore crucial to the success of any cancer screening 91

Pathogenesis and Prevention Cluster

programme. Establishment of screening registries and linkage of individual screening data with cancer registry data, taking into account appropriate data protection standards and methods, are essential tools for monitoring and evaluation. A major aim of the Screening Quality Control Group during the biennium has been to promote such activities through coordination of cancer screening guideline development and networking. Guideline development activities have been facilitated by consolidation of the former European breast and cervical cancer screening networks established under the Europe Against Cancer Programme in the European Cancer Network, which is coordinated by the Group. Guidelines for population-based breast cancer screening An updated and expanded fourth edition of the European Guidelines for Quality Assurance in Breast Cancer Screening and Diagnosis has been completed and has been published by the European Commission. The EU Guidelines are widely recognised as an international reference document for breast cancer screening and have improved the standards for safe and effective services through an organised, population-based approach. Physico-technical quality control of medical equipment has eliminated high dose exposure, epidemiological harmonisation has improved reporting, and training and service standards including multidisciplinarity have improved cancer early detection, diagnosis and management. Quality assurance has protected women from harm due to unnecessary additional procedures and has been an essential tool in delivering optimal services to women attending cancer screening. Since adhering to the European standards and recommendations provides for safe and effective screening, responsible authorities have a blueprint for development of national agreements and regulations which substantially simplifies commissioning of screening programmes. The scope of the extensive multidisciplinary guidelines has been

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extended to also cover multidisciplinary aspects of diagnosis as well as specialist breast units for clinical management of breast lesions. The updated breast screening guidelines are therefore expected to have a positive impact not only on the quality of breast cancer screening but also on the diagnosis and clinical management of breast lesions. Guidelines for population-based cervical cancer screening An expanded and updated second edition of the European Guidelines for Quality Assurance in Cervical Cancer Screening has been prepared and will be delivered shortly to the European Commission for publication. Cervical cytology is still the cornerstone of cervical cancer prevention programmes in Europe, although new perspectives for other screening technologies are developing rapidly. The principles of quality assurance, performance monitoring and evaluation, and many of the procedures and methodological standards laid down in the current guideline edition, are of equal relevance to cervical cancer screening based on other conceivable methods. It is therefore expected that the publication of the updated and revised second edition will also promote rigorous standards in the evaluation and application of new screening technologies, thereby improving the effectiveness of cervical cancer prevention in Europe. Over the short and medium term, screening for cervical cancer precursors and management of screen-detected lesions will remain the most effective tool for cervical cancer prevention in Europe. However, the field of cervical cancer prevention is rapidly developing due to better understanding of the natural history of the disease. Primary prevention by prophylactic vaccination against the HPV types that are causally linked with most cervical cancers is likely to become a feasible option for cervical cancer control, provided the current cost of inoculation regimens is substantially reduced. While prophylactic vaccination, primarily in young girls, may provide important future health gains,

cervical screening will need to be continued. Neglecting cervical cancer screening due to the current availability of a vaccine could paradoxically lead to an increase in cancer cases and deaths. Development of comprehensive European cervical cancer prevention guidelines that appropriately integrate screening and vaccination strategies is a key aim of the next phase of guideline development activities supported by the EU Public Health Programme. Guidelines for population-based colorectal cancer screening Development of the first edition of European Guidelines for Quality Assurance in Colorectal Cancer Screening is currently being coordinated by the Screening Quality Control Group. The project is conducted in partnership with the University of Oxford; the CPO Piemonte (Centre for Cancer Prevention) of Turin; the European Cancer Patient Coalition, Utrecht; and the Public Association for Healthy People, Budapest. The comprehensive guidelines developed in the project will be based on available evidence and previous experience in testing and quality assurance of colorectal cancer screening. They will cover the entire screening process from invitation to management of screen-detected lesions and will include recommendations for standardized procedures, monitoring and evaluation, as well as recommendations on future prospects for colorectal screening. Reporting on implementation of cancer screening The substantial potential of the current group activities to promote international collaboration in descriptive epidemiology and evaluation of cancer screening programmes is demonstrated by the panEuropean consensus recently established within the European Cancer Network on the need for a periodic international status report on cancer screening based on systematic collection and processing of individual data. The Group is currently collaborating with the Screening (SCR), Descriptive Epidemiology Production (DEP) and Data Analysis and Interpretation (DEA) groups at IARC in

Screening Quality Control Group

network activities. An initiative of high priority has been pursued in collaboration with the DEA group in the framework of the EUNICE project: an initial status report will provide the basis for future continuous updating of the implementation of screening programmes in the EU. The methodology developed and applied in this project can be expanded to systematic reporting on screening activities in other regions and will lay the foundation for future monitoring and evaluation of screening programmes.

European guidelines for quality assurance in cervical cancer screening S e c o n d E d i t i o n

European Commission

Future Guideline development activities In the framework of a grant provided by the European Communities (DG SANCO and Public Health Executive Agency) the mandate of the Group to coordinate development and updating of European Guidelines for breast and cervical cancer screening has been extended for another three years. The extended guideline development project will be a landmark activity because it recognises the substantial positive impact that EU guidelines for breast cancer screening have had on the delivery not only of service screening, but also diagnosis and management of breast disease across Europe. By likewise extending the scope of the cervical cancer screening guidelines, albeit to include a rapidly developing field of primary prevention, the updated guidelines are expected to help the numerous EU member states and applicant countries to develop a joint strategy to maximise the potential benefit of HPV vaccination in cervical cancer prevention. The guideline development work package for HPV vaccination will be led by the Head of the Infections and Cancer Epidemiology (ICE) Group.

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Pathogenesis and Prevention Cluster

The ECN Group is grateful to the following for their collaboration in its projects: Reinhard Horvat, Barbara Schleicher, Theresia Unger, Helene G. Wiener, Vienna, Austria; Marc Arbyn, Pieter Vandenbulcke, Brussels; Hilde Bosmans, Leuven; Karen Fredrix, Anne Vandenbroucke, Belgium; Shemuel Danon, Sofia, Bulgaria; Magdalena Grce, Zagreb, Croatia; Maria Nicolaïdou, Vayios Partassides, Larnaca; Pavlos Pavlou, Nicosia; Marija Petković, Cyprus; Adam Svobodnik, Brno; Jan Danes, Ruth Tachezy, Prague; Miroslava Skovajsova, Czech Republic; Elsebeth Lynge, Copenhagen, Denmark; Auni Aasmaa, Tallin, Estonia; Ahti Anttila, Nea Malila, Pekka Nieminen, Martti Pamilo, Helsinki; Matti Hakama, Tampere; Peter B. Dean, Turku, Finland; Christine Bergeron, Cergy-Pontoise; Philip Davies, Lyon; Patrice Heid, Brigitte Seradour, Marseille; Cédric Mahé, Paris; Jean-François Rey, St Laurent du Var; Rosemary Ancelle-Park, St Maurice; Jean-Jacques Baldauf, Muriel Fender, Strasbourg, France; Michael Vieth, Bayreuth; Monika Mund, Berlin; Wolff Schmiegel, Bochum; Anthony B. Miller, Heidelberg; Jan-Sebastian Graebe-Adelssen, Köln; Meinhard Classen, Ulrich Schenck, Munich; Margrit Reichel, Wiesbaden, Germany; Elena Riza, Athens, Charles Anthony, Ormylia, Emmanuel Diakomanolis, Greece; Szilvia Madai, Zoltan Péntek, Laszlo Vass, Budapest, Hungary; Walter Prendiville, Coombe; Niall Phelan, Dublin; Marian O'Reilly, Limerick, Ireland; Mauro Risio, Candiolo-Torino; Marco Zappa, Florence; Susan Ballenger Knox, Milan; Livia Giordano, Guglielmo Ronco, Nereo Segnan, Carlo Senore, Turin, Italy; Ludmila Engele, Riga, Latvia; Juozas Kurtinaitis, Vilnius; Viaceslavas Zaksas, Lithuania; Ferid Shannoun, Astrid Scharpantgen, Luxembourg; Miriam Dalmas, Malta; Solveig Hofvind, Elisabete Weiderpass, Oslo, Norway; Barbara Dabrowska, Wenancjusz Domagala, Andrej Nowakowsky, Poland; Antonio Morais, Vitor Rodrigues, Daniel Da Silva, Coimbra, Portugal; Luciana Neamtiu, Florian A. Nicula, Cluj, Romania; Vakhtang Merabishvili, Vladimir Semiglazov, St. Petersburg, Russian Federation; Kamil Pohlodek, Darina Sedlakova, Bratislava, Slovakia; Mateja Krajc, Maja Primic Zakelj, Ljubljana, Slovenia; Nieves Ascunce Elizaga, Pamplona; Montserrat Corujo Quinteiro, Santiago de Compostela; Dolores Cuevas, Lola Salas Trejo, Valencia; Raquel Zubizarreta, Spain; Joakim Dillner, Malmö; Lennarth Nystrom, Umea; Pär Sparen, Uppsala; Sven Törnberg, Stockholm, Sweden; Chris de Wolf, Fribourg, Switzerland; Paul Klinkhamer, Eindhoven; Mireille Broeders, Johan Bulten, Roland Holland, Erik Puthaar, Henny Rijken, Martin Thijssen, Nijmegen; Jacques Fracheboud, Iris Vogelaar, Rotterdam; Lynn Faulds Wood, Utrecht, The Netherlands; Caner Fidaner, Turkey; Joseph Jordan, Birmingham; Bob Steele, Dundee; Euphemia McGoogan, Edinburgh; Stephen Halloran, Kenneth Young, Guildford; Pierre Martin-Hirsh, Lancaster; Amanda Herbert, Nick Perry, Anne Szarewski, Clive Wells, London; Joan Austoker, Julietta Patnick, Premila Webster, Oxford, United Kingdom Financial support from the following bodies is gratefully acknowledged: European Union Public Health programme (grant no. 2004309) (The European Cancer Network) European Union Public Health programme (grant no. 2005317) (Development of European Guidelines for Quality Assurance of Colorectal Cancer Screening) European Union Public Health programme (grant no. 2004114) (EUNICE: European Network for Information on Cancer) European Union Public Health programme (grant no. 2006322) (European Cooperation on Development of Cancer Screening and Prevention Guidelines)

Publications Original papers Arbyn M, Primic-Zakelj M, Raifu O A, Grce M, Paraskevaidis E, Diakomanolis E, Kesic V, Nicula A F, Suteu O, von Karsa L (2007). The Burden of Cervical Cancer in South-East Europe at the Beginning of the 21st Century, Coll Antropol 31: Suppl. 2; 7-10.

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Books

Book chapters

European Commission (2006). European Guidelines for Quality Assurance in Breast Cancer Screening and Diagnosis. Fourth edition. Perry N, Broeders M, de Wolf C, Törnberg S, Holland R., von Karsa L, Puthaar E (eds). Office for Official Publications of the European Communities, Luxembourg.

Becker N, Karsa Lv (2006). Sekundäre Prävention (Krebsfrüherkennung) [Secondary Prevention (Cancer Screening)]. Schmoll H-J, Höffken K, Possinger K (eds) Kompendium Internistische Onkologie [Compendium of Oncology in Internal Medicine], 4th edition, Springer Medizin Verlag, Heidelberg; 1: 307339.

IARC Communications Group (COM)

Head Dr Nicolas Gaudin

Librarian Ms Sharon Grant

Secretary Ms Bernadette Geoffre

Technical Assistants Ms Latifa Bouanzi Ms Susan Cotterell (until March 2006) Mr Roland Dray Mr Georges Mollon

Editor Mr John Daniel The Communications (COM) Group has responsibility for the presentation of a homogeneous image of all aspects of IARC work to the scientific community, the media and the general public, as well as providing a service to the research Groups in all matters related to information. Publications/editing service The COM Group continues to assist all scientific Groups in disseminating their research results by providing editorial advice and help for publication of articles, papers and op-ed pieces in international scientific journals, supported by adequate graphic services, both for illustrations of publications and posters, and for the layout of the finished products, ready for printing. The dissemination of IARC publications has been passed on to our parent Organization exclusively. Under the IARC imprint, and in the period under review, the Agency completed publication of Volume 11 of the IARC Handbooks of Cancer Prevention, entitled Reversal of Risk after Quitting Smoking, three Working Group Reports (Volume 1, Exposure to Artificial UV Radiation and Skin Cancer, Volume 2, Common Minimum Technical Standards and Protocols for Biological Resource Centres Dedicated to Cancer Research, and Volume 3, Attributable Causes of Cancer in France in the Year 2000), five IARC Monographs on the Evaluation of Carcinogenic Risks to Humans (Volume 86, Cobalt in Hard Metals and Cobalt Sulfate,

Gallium Arsenide, Indium Phosphide and Vanadium Pentoxide, Volume 87, Inorganic and Organic Lead Compounds, Volume 88, Formaldehyde, 2-Butoxyethanol and 1-tertButoxy-propan-2-ol; Volume 89, Smokeless Tobacco Products, and Volume 90, Human Papillomaviruses, have been posted on the IARC website in digital format, before being printed). It has also made available free and public access to the update of Cancer Incidence in Five Continents, Volume IX of the series, through the Descriptive Epidemiology server on the IARC website. IARC also published Volume 1 of the 4th Edition of the WHO Classification of Tumours, dedicated to the Central Nervous System. Meanwhile, the third edition of this series continues to elicit interest, and is being reprinted extensively, as demand does not seem to dwindle, and a Chinese edition of the ten-volume 3rd edition has now been developed. Web services The COM Group maintains the Agency's bilingual internet site. The Group also manages the intranet service, which provides staff with many administrative resources, and maintains several central databases for the Personnel and Finance offices. This website is being upgraded to accommodate a modern communications strategy, in line with state-of-the-art technology and web 2.0 functionalities.

Mrs Josephine Thevenoux Ms Maria de la Trinidad Valdivieso Gonzalez

Public relations The Public Relations Service ensures relations between the Agency and the media, writing and distributing press releases, and organising press conferences. By means of a database of media contacts around the world, the service dispatches press releases to about 2700 e-mail addresses, press agencies, individual journalists and decision-makers. The impact of this effort is evident from the news coverage raised by several releases over the biennium that made headlines around the world. This service coordinates the issue of press releases on new evaluations within the Monographs programme with publication of a summary in the Lancet Oncology Policy Watch section, which offers the Agency a regular tribune for independent and transparent results. Translation The Translation Service provides translations from English to French of all official documents of the Governing Council and Scientific Council of IARC, as well as articles, technical documents, correspondence, memoranda and other texts for all the scientific and administrative Groups. It also organises successful language courses in both working languages for the Agency’s staff, as well as administering the United Nations language proficiency examinations.

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IARC Communications Group

Library The Library supports the information and research needs of IARC scientists through a wide range of electronic resources, a traditional print library collection, and by providing responsive, user-centred reference and instructional services. Desktop access to electronic information is facilitated by participation in resourcesharing and collaborative programmes

Communications Staff

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with the WHO Library and Information Networks for Knowledge. The Library’s Intranet website is the gateway for the delivery of information services and resources to the IARC community, and it too is being redesigned to accommodate more functionality and respond to growing needs of modern research. This provides access to the library catalogue, electronic journals, databases, electronic reference

resources and document delivery services. The IARC Library also responds to external needs by providing reciprocal services to specialised libraries in Lyon and by welcoming reference enquiries from the public.

Education and Training

Education and Training Research training is one of the key elements of the IARC Mission, and IARC has had a successful Education and Training Programme since its inception in 1966. The programme is currently organized in two major components: Training Courses and Fellowships. Training Courses The aim of the IARC Training Courses is to stimulate cancer research by improving scientific knowledge and developing skills among researchers worldwide. In 2005, a major evolution of courses was implemented, with the aim to increase the number of researchers trained every year and to broaden the research subjects covered. The different courses organized by

IARC in Lyon and in other locations have been combined to form a Summer School, lasting 4 weeks during June and July. Special attention is now given to low- and medium-resource countries, where opportunities for training in cancer research are limited. Helping to develop local expertise and strengthening research institutions through international collaborations are key components of the IARC strategy toward cancer control worldwide. IARC Summer School Both introductory and advanced courses are now offered within the framework of the IARC Summer School. In 2005, the Summer School offered three introductory modules (one-week duration each) on

Cancer Registration, Methods in Descriptive Epidemiology and Methods in Analytical Epidemiology. These were followed by two advanced modules on Environmental Cancer Epidemiology and Analysis of Time Trends. In 2006, the three introductory modules were repeated and the two advanced modules were Molecular Cancer Epidemiology and Survival Analysis Methods for Cancer Registries. In 2007, the first module remained Cancer Registration, while the second module developed into a two-week course on Introduction to Cancer Epidemiology. There was one advanced module on Genetic Epidemiology and Biobanking. The programme is advertised towards the end of each year and has recorded up to 250 applications. About half of the suitable

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Education and Training

candidates are retained on the basis of their background, their involvement in cancer research and the potential benefit of the training for their own institute and country. Participation in one or more modules is possible, depending on the interest and expertise of the applicants and availability of resources. Financial support for the Summer Schools has been received from the U.S. National Cancer Institute, the European Commission (through the ECNIS Network of Excellence), the International Atomic Energy Agency, the Alliance for Cervical Cancer Prevention and several Regional Offices of the World Health Organization. In 2006, the three introductory modules, Cancer Registration, Methods in Descriptive Epidemiology and Methods in Analytical Epidemiology were repeated. The two advanced modules were Molecular Cancer Epidemiology and Survival Analysis Methods for Cancer Registries. Overall there were 98 participants from 51 different countries: Albania (1), Belarus (1), Brazil (2), Brunei (1), Chile (1), China (3), Colombia (1), Cuba (1), Egypt (2), Gambia (1), Germany (1), India 98

(8), Iraq (1), Ireland (1), Italy (2), Jordan (1), Kenya (1), Korea (1), Kyrgyz Republic (1), Lebanon (1), Malaysia (1), Netherlands (1), New Zealand (1), Peru (1), Poland (1), Portugal (1), Romania (1), Russia (3), Rwanda (1), Saint Lucia (1), Serbia (1), Singapore (1), Slovakia (1), Slovenia (1), South Africa (1), Spain (1), Sri Lanka (2), Sudan (2), Sweden (1), Switzerland (3), Tanzania (1), Thailand (2), Turkey (1), United Kingdom (3), USA (1), Vietnam (1), Zambia (1). Of these, 71 participants were from low- and mediumresource countries and 64 received partial or full financial support. IARC participants originated from Brazil, China, France, Germany, India, Iran, Italy, Jordan, Netherlands, Pakistan, Sweden, Tajikstan. There were a total of 78 participants from 48 countries in 2007: Albania (2), Belarus (1), Botswana (2), Brazil (4), China (3), Cuba (1), Egypt (1), Estonia (1), France (2), Germany (1), Ghana (1), Greece (2), India (1), Indonesia (1), Iran (2), Iraq (1), Ireland (1), Italy (1), Jordan (1), Kenya (2), Korea (1), Luxembourg (1), Malaysia (2), Mongolia (3), Nepal (1), Nicaragua (1), Nigeria (1), Peru (1), Poland (2), Romania (2), Saudi Arabia (2), Serbia

(1), Spain (1), Sudan (1), Tanzania (1), Thailand (2), Ukraine (1), United Arab Emirates (1), United Kingdom (3), USA (1), Viet Nam (2), Yemen (1) and Zimbabwe (1). A total of 51 participants were from low- and medium-resource countries, and 45 received partial or full financial support. IARC participants originated from Armenia, China, Estonia, France, Germany, Italy, Norway, Poland, South Africa, Sweden, Switzerland and Viet Nam. Students’ evaluation, comments and suggestions were collected by means of an anonymous questionnaire returned at the end of each module. Overall there was a high level of satisfaction. Regional Course on Cancer Registration, Johannesburg, South Africa, 14-22 March 2006 This course for African countries was held in conjunction with the WHO Regional Office for Africa, with support from the National Cancer Institute of the USA. The programme covered all aspects of cancer registration with particular emphasis on abstracting and coding tumour data according to the ICD-O(3) and summary stage SEER systems.

Education and Training

There were 35 participants from 19 countries (Angola, Botswana, Cameroon, Eritrea, Ethiopia, Gambia, Ghana, Kenya, Malawi, Mauritius, Mozambique, Namibia, Nigeria, South Africa, Sudan, Swaziland, Tanzania, Zambia and Zimbabwe). These represented 17 operative registries, 3 hospital/pathologybased, and 3 planned (Sudan, Eritrea and Ethiopia). Molecular Cancer Epidemiology Course, Seoul, Republic Of Korea, 12-15 September 2006 The course was held in conjunction with the National Cancer Center of the Republic of Korea and the Korean Society for Genomic Epidemiology. The aim was to review methodological and substantive issues in the current practice of molecular cancer epidemiology and to provide the participants with basic tools to develop their own research. Priority was given to participants from Asia and the Pacific. There were 27 participants from seven countries (India, Japan, Korea, Malaysia, Mongolia, the Philippines and Switzerland).

Cancer Research Fellowships Post-doctoral fellowships The main component of the Fellowship Programme consists of Post-doctoral Fellowships awarded to young researchers to come to IARC. Each year 10–12 young scientists are awarded research training fellowships in areas ranging from biostatistics and epidemiology to mechanisms of carcinogenesis. Heavy demand means there is strong competition, and fellows are chosen by a selection committee of both IARC and external scientists. At the time the Fellowship Programme was established, and for a significant period of time thereafter, an IARC Fellowship was one of the few ways to obtain training in cancer research in a major institute in another country. Between 1966 and 2004, over 500 such fellowships were awarded to talented young scientists from over 60 countries. With the general increase in the availability of cancer research fellowships for high-quality students from highresource countries, the programme was restructured in 2004 to allow IARC to make a unique contribution by focusing on

students and junior cancer researchers from low- and medium-resource countries, where training in cancer research is rarely available. This new focus also allows the Agency to nurture international collaboration in those aspects of cancer research related to its own programme by providing for the training at the Agency of young scientists from low- to mediumresource countries who wish to pursue a career in cancer research. Post-doctoral fellowships are awarded for one year, and can be extended to a second year pending satisfactory performance. A small grant towards starting a collaborative research project is awarded to selected fellows upon completion of their fellowship. To date, 27 postdoctoral fellowships have been awarded, 30% in the field of epidemiology and 59% from Asia, since the inception of the new programme, and 6 new fellowships were awarded in 2007 while 4 were extended for another year. In the 2006–2007 biennial period, two-year postdoctoral Fellowships were awarded to junior scientists from Brazil, India, Pakistan, the People’s Republic of China, Poland and Serbia.

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Education and Training

The IARC fellowships are partially supported by the Italian Association for Research on Cancer. Master’s/PhD Fellowships (up to four years) The first PhD Fellowship has been awarded to a junior scientist from Iran, under joint supervision with King’s College London, UK. Expertise Transfer Fellowship This fellowship enables an established and experienced investigator to spend from six to twelve months in an appropriate host institute in a low- to medium-resource country in order to transfer knowledge and expertise in a research area relevant to the host country and related to the Agency’s programme. In 2006, the fellowship was awarded to Professor Bo Lambert (Department of Biosciences, Karolinska Institute, Huddinge, Sweden) to spend a total of six months in the Faculty of Medicine, Makerere University, Kampala,

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Uganda, and in 2007 to Dr Elisabete Weiderpass-Vainio (Cancer Registry of Norway, Oslo, Norway) who will spend 2 months at Makerere University. Visiting Scientist Award In 2006, this Award was given to Dr Harvey Checkoway (Department of Environmental and Occupational Sciences, University of Washington, Seattle, WA, USA) who spent 7 months in the Lifestyle, Environment and Cancer Group, and Dr Anna Barón (Department of Preventive Medicine and Biometrics, University of Colorado School of Medicine, Denver, CO, USA), who spent 3 months in the Infections and Cancer Epidemiology Group. In 2007 the Award has been given to Dr Kunnambath Ramadas (Regional Cancer Centre, Trivandrum, India), and to Dr Maqsood A. Siddiqi (Cancer Foundation of India, Kolkata, India) who will spend one year

and three months, respectively, in the Screening Group. Trainees, students, postdocs and senior visiting scientists at IARC In keeping with the Agency’s mission to provide education and training in the field of cancer research, as well as to provide appropriately qualified persons with training and experience in cancer research and related support areas at IARC in positions that provide some complementary support to the Agency’s activities, in addition to the fellowship programme, IARC continues to welcome a substantial number of trainees, master’s/doctoral students, technical students, postdocs and visiting scientists each year (between 70 and 80), who come with either outside funds or who are funded in part or in total by the Agency.

Division of Administration and Finance OFFICE OF THE DIRECTOR OF ADMINISTRATION AND FINANCE Director of Administration and Finance Mr Michael Johnson Administrative Officer Ms Virginie Vocanson Clerk Ms Sophie Sibert-Dardenne Assistant (Documents) Ms Agnès Meneghel Administrative Assistant (Central Secretarial Services, CSS) Ms Susan Anthony Clerks (CSS) Ms Karima Abdedayem Ms Silvia Araujo de Lima Ms Catherine Benard Ms Dominique Navas (until July 2006)

ADMINISTRATIVE SERVICES OFFICE Administrative Services Officer Mr Gérard Guillerminet Administrative assistant Ms Sophie Servat Assistant (Supplies) Ms Fabienne Lelong Assistant (Registry) Ms Anne-Magali Maillol Support Staff Mr Patrice Barbieux Mr Michel Bazin Mr Jean-Paul Bonnefond Mr José Cardia Lima (from July 2007) Ms Odile Drutel Mr Jean-Francois Durand Gratian (until June 2006) Ms Jessica Fournera (from February 2007) Mr William Goudard Mr Antoine Hernandez (from July 2006) Mr Michel Javin Ms Rita Kibrisliyan Ms Sandrine Macé Ms Michèle Marsal (until January 2007) Ms Linda Monnerat (until March 2006) Ms Sara Morcillo Llerena (from November 2007) Mr Ludovic Ripert Ms Séverine Sarboni (from March 2006)

PERSONNEL OFFICE Personnel Officer Ms Raymonde Alloin Assistant Ms Eve El Akroud Support staff Ms Maud Bessenay Ms Isabelle Poncet Secretary to IARC Staff Association Committee Ms Christine Mogenet Social Adviser Mr Henri Paraton (until July 2007) Ms Sophie Beslay Deveze (from September 2007) Staff Physician Dr Annie Robert

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The IARC Ethics Review Committee (ERC) and Institutional Review Board (IRB) At its 47th Session, held in May 2005, the Governing Council of the International Agency for Research on Cancer approved a resolution making fundamental changes to the arrangements for ethics review and procedures at the Agency (GC/47/12 Rev. 1). Two distinct components were envisaged: an Institutional Review Board and an Ethics Review Committee. The IARC Institutional Review Board (IRB) The IRB is composed of nine members from a variety of backgrounds all of whom were nominated and appointed by the Chairman of the Governing Council. Five members come from outside the Agency and four from the Agency staff: • Professor Jean-Pierre Boissel • Dr Paul Brennan (IARC) • Mrs Mireille Guigaz (Chair) • Mrs Ghislaine Martel-Planche (IARC) • Mr Bernard Pedeux • Dr Martyn Plummer (IARC) • Professor Maxime Seligmann • Dr Pierre-Jean Souquet • Dr Bakary Sylla (IARC) The IRB meets in Lyon every two months to evaluate IARC project proposals, and has the authority to approve or disapprove a protocol or to require modifications to a protocol as a condition for approval, to suspend or terminate a study, or to impose restrictions or require modifications to a study as a condition for continuation. An IARC ethics website has been created (http://ethics.iarc.fr/) to provide all necessary information to IARC scientists about IRB project submission (questionnaire), governance documents and ethical issues. Regular IRB meetings

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started at IARC on 1 February 2006; to date 59 project proposals have been evaluated. Of these, 58 were given ethical clearance or provisional clearance subject to receipt of further documentation and 1 project proposal was rejected. Professor Charles Gillis, former Chairman of the National Multicentre Research Ethics Committee for Scotland, UK, and who was responsible for establishing the present ethics committees system at IARC, acts as IRB Convenor and advises IARC staff and IRB members on any matters of ethical concern. The IARC Ethics Review Committee (ERC) The ERC is composed of nine senior members from the international community, also nominated by the Governing Council, which includes the Chair of the IRB: • Dr Kazem Behbehani (Kuwait) • Mr David Byrne (Ireland) (Chair) • Professor Ketayun Dinshaw (India) • Mrs Mireille Guigaz (France; Chair, IRB) • Lord James Mackay (United Kingdom) • Professor Edith Olah (Hungary) • Professor Jae-Gahb Park (Republic of Korea) • Dr Luis Pinillos Ashton (Peru) • Dr Ebrahim Malik Samba (Gambia) The ERC was created in order to bring its global expertise to answer certain controversial issues within project proposals and to monitor the work of the IRB. This committee meets twice per year, with one meeting being held in Lyon in conjunction with a monthly IRB meeting in order for the two committees to consult

on matters of concern. The other yearly meeting takes place in turn in one of the WHO Regions where IARC has on-going scientific activity. On 11–12 January 2007, the ERC meeting was hosted by Dr Luis Pinillos Ashton in Lima, Peru. Topics discussed included ethics in low- and mediumresource countries, monitoring of projects by the IRB, collaboration between the IRB and ERC, ethics committees training, funding from industrial sources and the creation of a Data Monitoring and Safety Committee for two randomized screening trials undertaken by the Agency. The next ERC meeting will take place in Mumbai, India on 16–17 January 2008 and will be hosted by Professor Ketayun Dinshaw, Director of the Tata Memorial Centre. Joint Meetings Two joint meetings with the ERC and IRB took place in June 2006 and October 2007. Subjects discussed included the remit of each committee and the possibility of appeal, the composition of the IRB and the balance between external and internal members, IRB decisions and quorum, consent of minors and IARC ethics documents. A set of Standard Operating Procedures (SOPs) and Rules and Procedures (RAPs) have been drawn up and were recently revised. After finalisation, these will be published on the IARC website. IARC Scientific Coordinator In November 2006, Mr Markus Pasterk was appointed IARC Scientific Coordinator. He works closely with the IRB and ERC Chairs and is responsible for ensuring that all relevant IARC project proposals go through the ethics process.

Ethics Review Committee and Institutional Review Board

Conclusion The deliberations of the IRB are carried out in a detailed and careful manner. A number of decisions have been taken since the commencement of its work applying appropriate ethical principles. The IARC is fortunate to have people of such calibre available who can provide their valuable

services at short notice to assist the work of the IRB. The deliberations of the ERC, whether working alone or jointly with the IRB, are wide-ranging with the intention of bringing a global perspective while being aware at all times that local conditions may present challenges in determining the

application of appropriate ethical guidelines. The members of the ERC provide the global perspective necessary to guide the IARC in its important work.

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IARC Governing and Scientific Councils IARC’s work is overseen by two governing bodies, the Governing Council and the Scientific Council. Governing Council The Council consists of representatives from the 20 Participating States which direct and support the Agency. The Director-General of WHO is an ex officio voting member of the Governing Council. The Council oversees the scientific programme of the Agency and its execution. It elects the Director and determines the biennial budget. The Council meets once a year in Lyon, usually in the week before the World Health

Assembly in Geneva. The Chairperson of the Governing Council prepares the meeting together with the secretariat and advises the Director throughout the year. Scientific Council The Scientific Council reviews the scientific activities of the Agency and advises the Director on research strategies, especially in setting priorities for future projects. The Scientific Council’s reports for the Governing Council form the scientific basis for Governing Council policy, in particular when considering the budget. Members of the Scientific Council are elected by the Governing Council on

the basis of their scientific expertise in areas relevant to the Agency’s activities. Budget For the biennium 2006–2007, the IARC Governing Council voted a regular budget of US$39.27 million. Of this, about 77% was allocated to research programmes. In addition to the regular budget, the Agency receives extrabudgetary funds, mainly through research grants, and to a lesser extent through donations. In the 2004– 2005 biennium, approximately 33% of the Agency's overall expenditure was financed by extrabudgetary funds.

Participating States and Representatives at IARC Governing Councils Forty-Eighth Session, 18–19 May 2006 Netherlands Dr J.-W. Hartgerink, Chairperson Ministry of Health, Welfare and Sport The Hague

Australia Professor J. Horvath Department of Health and Ageing Canberra

Norway Dr L.E. Hanssen, Vice-Chairperson The Norwegian Board of Health Oslo

Belgium Dr M. Haelterman SPF Santé publique, Sécurité de la Chaîne Alimentaire et Environnement Bruxelles

Dr B. Mørland, Alternate Norwegian Knowledge Center for the Health Services Oslo Dr H. Blankson, Alternate The Research Council of Norway Oslo Finland Professor P. Puska, Rapporteur National Public Health Institute – KTL Helsinki

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Canada Dr H. Bryant Institute for Cancer Research, CIHR Calgary Mr L.S. Mery Public Health Agency of Canada Ottawa Denmark Professor H. Autrup Institute of Public Health Aarhus

France Mme B. Guillemette Directrice des Relations Institutionnelles et Européennes Institut national du Cancer (INCa) Boulogne-Billancourt M. G. Delvallée Ministère des Affaires étrangères Paris Mme A. Jourdan-Roubaud Direction générale de la Santé Paris Germany Mr M. Debrus Multilateral Cooperation in the Field of Health Federal Ministry of Health Bonn

IARC Governing and Scientific Councils

India Mr P.K. Hota Ministry of Health and Family Welfare New Delhi

Dr J. Arribas President, Technical Cancer Barcelona

Mr K. Raamamoorthy Ministry of Health and Family Welfare (Cancer Division) New Delhi

Sweden Professor H. Billig Swedish Research Council – Medicine Stockholm

Italy Dr F. Belardelli Institut supérieur de la Santé Rome

Switzerland Dr G. Escher Secrétariat d’Etat à l’Education et à la Recherche Berne

Japan Dr S. Koike Ministry of Health, Labour and Welfare Tokyo Republic of Korea Dr Jong-Koo Lee Ministry of Health and Welfare Seoul

Committee

on

Dr S. Zobrist Office fédéral de la Santé publique Berne United Kingdom of Great Britain and Northern Ireland Dr D. Dunstan Medical Research Council London

Dr Hai-Rim Shin Research Institute for National Cancer Control & Evaluation Seoul Spain Ms Elena Martin-Asin Ministerio de Sanidad y Consumo Madrid

United States of America Dr M. Clanton US Department of Health and Human Services Bethesda, MD

Dr R.J. Coates US Department of Health and Human Services Atlanta, GA Dr J. Harford National Cancer Institute Bethesda, MD World Health Organization Dr R. Beaglehole Director – Chronic Diseases and Health Promotion Mrs J. McKeough Office of the Legal Counsel Dr A. Ullrich Programme on Cancer Control

Observers Dr B. Ponder Chairman, Scientific Council Dr J.D. Potter Outgoing Chairman, Scientific Council

External Audit Mr S.S. Pandey

Forty-Ninth Session, 10–11 May 2007 Norway Dr Lars E. Hanssen, Chairperson The Norwegian Board of Health Oslo Dr Henrietta Blankson The Research Council of Norway Oslo Australia Professor John Horvath, Vice-Chairperson Department of Health and Ageing (MDP 84) Canberra Switzerland Dr Gérard Escher

Secrétariat d’Etat à l’Education et à la Recherche Berne Dr Stéphanie Zobrist, Rapporteur Office fédéral de la Santé publique Berne Dr Diane Steber Büchli Office fédéral de la Santé publique Berne Belgium Ms Leen Meulenbergs SPF Santé publique, Sécurité de la Chaîne alimentaire et Environnement Bruxelles

Canada Dr Philip E. Branton CIHR Institute of Cancer Research Montreal, Quebec Mr Nick Previsich Health Canada Ottawa, Ontario Ms Lianne Vardy Public Health Agency of Canada Ottawa, Ontario Denmark Professor Herman Autrup University of Aarhus Aarhus 105

IARC Governing and Scientific Councils

Finland Professor Pirjo Pietinen National Public Health Institute Helsinki France Madame Pascale Flamant Institut national du Cancer (INCa) Boulogne-Billancourt Madame Brigitte Guillemette Institut national du Cancer (INCa) Boulogne-Billancourt M. Guillaume Delvallée Ministère des Affaires étrangères Paris Dr Elisabeth Gaillard Direction générale de la Santé Paris M. Eric Postaire Direction générale de la Recherche et de l’Innovation Paris

Ministry of Health, Labour and Welfare Tokyo Dr Tomohiko Makino Ministry of Health, Labour and Welfare Tokyo Netherlands Dr Jan Willem Hartgerink Ministry of Health, Welfare and Sport The Hague Mr Jeroen Hulleman Ministry of Health, Welfare and Sport The Hague Republic of Korea Mr Hee-Joo Choi Ministry of Health and Welfare Seoul Mr Gyeong-Hun Park Ministry of Health and Welfare Seoul

Madame Géraldine Bonnin Ministère de la Santé et des Solidarités Paris

Russian Federation Mr Mikhail Zurabov Minister of Health and Social Development Moscow

Germany Mr Michael Debrus Federal Ministry of Health Bonn

Dr Lev Scherbakov Ministry of Health and Social Development Moscow

India Dr Bhavani Thyagarajan Ministry of Health and Family Welfare New Delhi

Dr Oleg P. Chestnov Department of International Collaboration and Public Relations Ministry of Health and Social Development Moscow

Ireland Dr James Kiely Department of Health and Children Dublin Dr Tony Holohan Department of Health and Children Dublin Italy Dr Filippo Belardelli Institut supérieur de la Santé Rome Japan Dr Hajime Inoue 106

Ms Nadezda Kuleshova Department of International Collaboration Moscow Spain Dr Carlos Segovia Ministerio de Sanidad y Consumo Madrid Dr Marina Pollán Santamaría National Epidemiology Centre Madrid

Dr Juan Barbera Rives Secretaria General de Sanidad Madrid Sweden Professor Karin Forsberg Nilsson Swedish Research Council – Medicine Stockholm United Kingdom of Great Britain and Northern Ireland Dr Mark Palmer Medical Research Council London United States of America Ms Mary Lou Valdez US Office of Global Health Affairs Rockville, MD Dr Ralph J. Coates Cancer Division, Centers for Disease Control US Department of Health and Human Services Atlanta, GA World Health Organization Mrs Joanne McKeough Office of the Legal Counsel Dr Benedetto Saraceno Acting Director, Chronic Diseases and Health Promotion (CHP) Dr Andreas Ullrich Cancer Alliances Observers Dr Bruce Ponder Chairman, Scientific Council Dr Jack Siemiatycki Chairman, 43rd Session Scientific Council Dr David Byrne Chairman, IARC Committee

of

Ethics

IARC

Review

International Union Against Cancer Dr Roberto Zanetti (unable to attend) CPO – Piedmont Cancer Registry Torino

IARC Governing and Scientific Councils

Members of Scientific Council (2006) Switzerland

Dr F. Amalric Institut National du Cancer France

Dr E. Lund University of Tromsø Norway

Dr H. Autrup University of Aarhus Denmark

Dr M. Pierotti Istituto Nazionale Tumori Italy

Dr J. Baselga Vall d´Hebron University Hospital Spain

Dr Pirjo Pietinen National Public Health Institute Helsinki

Dr W. Boecker University of Münster Germany

Dr B.A. Ponder CR UK Department of Oncology UK

Dr A. Burny Faculté des Sciences agronomiques Belgium

Dr J.D. Potter Fred Hutchinson Cancer Research Center USA

Dr J. Jiricny University of Zürich

Dr J. Siemiatycki Université de Montréal Canada Dr R.L. Sutherland Garvan Institute of Medical Research Australia Dr R. Toftgård Karolinska Institute Sweden Dr Flora van Leeuwen The Netherlands Cancer Institute The Netherlands Dr K. Wakabayashi National Cancer Center Research Institute Japan

Members of Scientific Council (2007) Dr F. Amalric Institut National du Cancer France Dr J. Baselga Vall d´Hebron University Hospital Spain Dr W. Boecker University of Münster Germany Dr A. Burny Fonds National Scientifique Belgium

de

Dr B. Kiemeney Radboud University Nijmegen Medical Centre The Netherlands Dr E. Lund University of Tromsø Norway Dr T.F. Ørntoft Aarhus University Hospital Denmark

la

Recherche

Dr R. Herrmann University Hospital Basel Switzerland Dr K. Husgafvel-Pursiainen Finnish Institute of Occupational Health Finland

Dr M. Pierotti Istituto Nazionale Tumori Italy Dr B.A. Ponder Cancer Research UK Cambridge Research Institute UK

Dr E. Ron National Cancer Institute, National Institutes of Health USA Dr J. Siemiatycki Université de Montréal Canada Dr R.L. Sutherland Garvan Institute of Medical Research Australia Dr R. Toftgård Karolinska Institute Sweden Dr K. Wakabayashi National Cancer Center Research Institute Japan

107

Meetings and Seminars Organised at IARC Meetings 16-17/01/2006 EUROCAN+PLUS Part 1 Kick-off Meeting 16/01/2006 Quality & comparability of descriptive cancer data: current challenges in the use of registry data

27/03/2006 Development of p53 peptide-based vaccines for immunotherapy of cancer

22/05/2006 Evaluating carcinogens: examples from the IARC Monographs

27/03/2006 Visit of Delegation from Republic of Ireland

01-02/06/2006 Relationship between paediatric CT exposure and cancer risk

06/04/2006 Biobanks in Europe

06-07/06/2006 ALPHA-RISK: Dosimetry Subcommittee meeting

17-18/01/2006 31st ENCR Steering Committee Meeting

07/04/2006 Gene-Rad-Risk: Project Board meeting

17/01/2006 Cancer incidence & survival patterns in a cohort of World War II survivors in Israel

10-11/04/2006 Defining the Upper Limits for Tobacco Toxicants: A joint WHO/TFI-IARC Working Group

26-27/01/2006 IARC working group on cancer following the Chernobyl accident 02-03/02/2006 42nd Session of the IARC Scientific Council 07-14/02/2006 Monograph Meeting, Vol. 93: Carbon black, titanium dioxide and nonasbestiform talc 28/02/2006 ECNIS - WP 7: Development and validation of biomarkers of individual susceptibility 06-07/03/2006 First EUNICE Steering Committee Meeting 13-20/03/2006 IARC Tobacco Control Handbook: "Reversal of Risk after Quitting Smoking" 14/03/2006 Eurocan+Plus WP10 Meeting 15/03/2006 Eurocan+Plus WP8 Meeting 108

25-26/04/2006 32nd ENCR Meeting

Steering

Committee

04-05/05/2006 IARC Working Group on a Code of Good Practice for IARC Research Studies 10-11/05/2006 Expression array analyses in breast cancer taxonomy 10-11/05/2006 European Cancer Mortality Atlas 15-16/05/2006 Workshop on Childhood Cancer 17/05/2006 IARC Scientific Day 22/05/2006 Cellular and Biochemical Characterization of tRNase Z, product of a candidate prostate cancer susceptibility gene 22/05/2006 Mechanisms of carcinogenesis: relevance to cancer hazard evaluation

08-09/06/2006 EPIC Steering Committee 08-09/06/2006 Joint IRB/ERC Meeting 13/06/2006 Eurocan+Plus Project Joint WP10 & WP11 Meeting 14-21/06/2006 IARC Monographs, Vol. 94: Ingested nitrates and nitrites, and blue-green algae toxins including microcyctin-LR and nodularin 19-23/06/2006 IARC Summer School, Registration Module

Cancer

22-23/06/2006 Epigenetics and Cancer Meeting 26-30/06/2006 IARC Summer School, Introduction to Descriptive Cancer Epidemiology Module 26-27/06/2006 GEMINI/Golestan meeting 03-07/07/2006 IARC Summer School, Introduction to Analytical Cancer Epidemiology Module 04-06/07/2006 Editorial Board Meeting for Cancer Incidence in Five Continents

Meetings and Seminars

04/07/2006 UV-France Kickoff Meeting 07/07/2006 Recent advances association studies

in

(BCAC) meeting

genomewide

10-14/07/2006 IARC Summer School, Molecular Cancer Epidemiology Module IARC Summer School, Survival Analysis Methods for Cancer Registries Module 19-21/07/2006 Meeting of National Cancer Institute Directors 05/09/2006 NORA/NIOSH/IARC Meeting

19-20/10/2006 Special Committee "Communication with Scientific Council" 20-21/10/2006 Consortium of Investigators of Modifiers of BRCA 1/2 (CIMBA) meeting 09/11/2006 GENE-RAD-RISK Project Board Meeting 09-10/11/2006 GENE-RAD-RISK Consortium Meeting 14/11/2006 Eurocan+Plus Work Package 10 Meeting

06-08/09/2006 Advisory group meeting to Plan Volume 100 of the IARC Monographs: A Review of Human Carcinogens

16-17/11/2006 2nd Meeting of the IARC Scientific Practice Working Group

12-13/09/2006 33rd Meeting of the ENCR Steering Committee

17/11/2006 Manuscript Publication question-andanswer session

12/09/2006 Molecular epidemiology testicular cancer in Europe

on

20-22/11/2006 2nd Meeting of the EUNICE Steering Committee

19-21/09/2006 ENCR Course on Cancer Prediction Methods

27-28/11/2006 Cancer Control and Capacity Building in Countries of Limited Resources

22/09/2006 Workshop on Cancer Projections

30/11/2006 To 01/12/2006 Scientific Review of Pathogenesis and Prevention Cluster (PPC) and Tobacco and Cancer Group (EBC/TOB)

study

10-17/10/2006 IARC Monographs, Vol. 95: Indoor air pollution from household heating and cooking: some solid-fuel and cooking-oil fumes 11-13/10/2006 3rd Editorial Board Meeting for Cancer Incidence in Five Continents: Volume 9 17-18/10/2006 International BRCA1/2 Carrier Cohort Study (IBCCS) Meeting 18-19/10/2006 Breast Cancer Association Consortium

04-05/12/2006 Alpha-Risk -Dosimetry Subcommittee Meeting 05/12/2006 Metropolitan economic Mission from Quebec/Mission économique métropolitaine de Québec

05-06/12/2006 Alpha-Risk: Epidemiology Subcommittee Meeting

08-09/12/2006 1st p53 IARC-KI Symposium 11-12/12/2006 Eurocan+Plus General Assembly 14-15/12/2006 Fifth Meeting of the Study Group of the Alcohol-related Cancers and Genetic Susceptibility in Europe (ARCAGE) 08-10/01/2007 INTERPHONE analysis task group meeting: RF exposure gradient 16-19/01/2007 4th Editorial Board Meeting for CI5 Vol. IX 17-18/01/2007 International Lung Cancer Consortium (ILCCO): The Fourth Annual Meeting 18-19/01/2007 SYNERGY: Pooled analysis of European case-control studies on interactions of occupational carcinogens in lung cancer development Kick-off meeting 18-19/01/2007 The International Head and Neck Cancer Epidemiology (INHANCE) Consortium 22-23/01/2007 Progresses in the identification of markers of human papillomavirus and helicobacter species 24/01/2007 Key role of IARC in descriptive cancer epidemiology 26/01/2007 International Association of Cancer Registries Management Meeting 30-31/01/2007 34th ENCR Steering Committee Meeting 05-06/02/2007 Paediatric CT exposure and cancer risk: Dosimetry and Epidemiology meeting 06-13/02/2007 Monograph Meeting, Vol. 96, Alcoholic beverage consumption, acetaldehyde and 109

Meetings and Seminars

urethane 06/02/2007 Vision for Basic Cancer Research

23-24/04/2007 Working Group on Burden of Cancer from Asbestos Exposure

15-16/02/2007 Workshop on Methodological Issues in the Design and Analysis of Gene and Environment Studies 19/02/2007 Réunion de coordination du projet multicentrique de communication: ExpoCancer Lyon 26-27/02/2007 Histoscanning for the early detection of breast cancer

Butadiene, Ethylene Oxide and Vinyl Halides (Vinyl Fluoride, Vinyl Chloride and Vinyl Bromide) 11-15/06/2007 IARC Summer School on Cancer Epidemiology, Module 1: Cancer Registration

24/04/2007 Visit of Senegalese Delegation 24-26/04/2007 5th Editorial Board Meeting for CI5 Vol. IX 25/04/2007 Imputation Methods for Adjusting for Covariate Measurement Error

18-29/06/2007 IARC Summer School on Cancer Epidemiology, Module 2: Introduction to Cancer Epidemiology

26-27/04/2007 EPIC Statistical Working Group Meeting

19/06/2007 Identifying genes that cause lung cancer: Results from linkage studies and plans for genomewide association studies

05-06/03/2007 Implementation of Cervical Cancer Screening in EU

02/05/2007 Eurocan+Plus WP10 Meeting

21-22/06/2007 Central Europe Multicenter Study Group

08-09/03/2007 EuroWorksafe Meeting

08/05/2007 Vitamin D Secretariat meeting

21-22/06/2007 EuroWorksafe meeting

11-13/03/2007 INTERPHONE Principal Investigators meeting

09/05/2007 IARC Scientific Day

28-29/06/2007 36th ENCR Steering Committee Meeting

09/05/2007 'Meet the Professor' session: Dr LaSalle D. Leffall, Jr; Professor Dimitrios Trichopoulos; Dr Mariano Barbacid

02-06/07/2007 IARC Summer School on Cancer Epidemiology, Module 3: Genetics Epidemiology

14/05/2007 Gene-Rad-Risk Project Board meeting

03-04/07/2007 6th Editorial Board Meeting for CI5 Vol. IX

12-19/03/2007 IARC Handbooks on Tobacco Control, Volume 2: Evaluating Effectiveness of Population-Based Tobacco Control 13-14/03/2007 Pooled Endotoxin and Cancer Study Meeting 16/03/2007 FP7 Grant Application on Nutrition and Ageing 27/03/2007 Environmental RF exposure assessment 29/03/2007 Lyon d'Abord: Visite de courtoisie de l'Association 11-12/04/2007 35th ENCR Steering Committee Meeting 16/04/2007 CI5: ICDO-3 Meeting

110

Histological

14-15/05/2007 The third Study Group meeting of the Nested case-control study of lung cancer among European asphalt workers 21/05/2007 Women in Europe Against Lung Cancer and Smoking (WELAS project kick-off meeting) 22/05/2007 Working Group Meeting to finalize the FP7 ERA-Net Grant Application to EU 23-25/05/2007 EPIC Working Groups Meetings: EPIC Steering Committee Meeting

06/07/2007 Vitamin D Secretariat Meeting 09-10/07/2007 Training Workshop on Methods and Guidelines for the Development of Mutation Databases in Cancer 09-10/07/2007 A translational worldwide perspective for liver cancer 10-11/07/2007 Dosimetry subcommittee ALPHA-RISK Study

meetings:

Groups 05-12/06/2007 IARC Monographs, Vol. 97:

1,3-

11/07/2007 Project Management Group Meeting:

Meetings and Seminars

Alpha Risk 11-13/07/2007 Meeting of the IARC Cancer Control Forum (National Cancer Institute Directors)

11-12/10/2007 Joint IRB/ERC Meeting 11/10/2007 Tumorotheque Nationale Virtuelle/ Programme d'Appui au PNES poumon

25/07/2007 Working Group on Data Production in Cancer Registration in Low- and Medium-Resource Countries

24/10/2007 ITS Review

03/09/2007 Eurosun Launch Meeting 10/09/2007 IARC-WHO Research Programmes 13-14/09/2007 RF Exposure Assessment Task Group meeting 18-20/09/2007 Annual Meeting of the International Association of Cancer Registries (IACR) 21/09/2007 Annual Meeting of the European Network of Cancer Registries (ENCR) 25-26/09/2007 Alpha-Risk WP4 27-28/09/2007 Workshop on errors in doses in radiation studies. 28/09/2007 Kick-off Meeting of International Study on Embryonal Tumours 01-02/10/2007 Orientation Session for new Scientific Council members 02-09/10/2007 IARC Monographs, Vol. 98, Fire-fighting, painting and shift-work 08-09/10/2007 3rd EUNICE Meeting

Steering

Committee

10/10/2007 Comité de Pilotage Radiofréquences

24-26/10/2007 Colorectal Cancer Screening Guideline Development workshop 25-27/10/2007 Editorial and Consensus meeting: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 29-30/10/2007 Working Group on Burden of Cancer from Asbestos Exposure 05-06/11/2007 Kick-Off meeting for NIH Occupation Study 08-09/11/2007 SYNERGY: Pooled analysis of European case-control studies on interactions of occupational carcinogens in lung cancer development: Second study group workshop 12/11/2007 Fourth Mutp53 Annual Meeting 13-15/11/2007 3rd International Mutant p53 Workshop 15-16/11/2007 Li-Fraumeni Syndrome Symposium 15-16/11/2007 Fourth Active p53 Annual Meeting 19-23/11/2007 International Chemical Safety Cards Meeting 19/11/2007 Eurocan+ Plus Final General Assembly 29-30/11/2007 Biostatistics and Epidemiology Cluster (BEC) Review

03-04/12/2007 Cancer in Africa, Asia, and Latin America: Improving Data Quality 05/12/2007 Working Group on Cancer Registration in PACT Countries 06-07/12/2007 2nd IARC Meeting on Epigenetics and Cancer 12-14/12/2007 Vitamin D Working Group 12/12/2007 Genome-wide association studies of prostate and breast cancer: The NCI CGEMS study 18/12/2007 Joint Cohort Studies Meeting Seminars 12/01/2006 Using linkage analysis to map prostate cancer susceptibility genes, can large families help? Dr James McKay 13/01/2006 Breast Cancer: from Mendelian Genetics to Genetic Epidemiology: Dr Olga Sinilnikova 16/01/2006 Quality & comparability of descriptive cancer data: current challenges in the use of registry data: Dr Paola Pisani 17/01/2006 Cancer incidence & survival patterns in a cohort of World War II survivors in Israel: Dr Micha Barchana 24/01/2006 "Cause of Death Statistics in the European Union - Eurostat Partnership on Health Statistics": Ms Mary Heanue 24/01/2006 Development of international standards for descriptive cancer data: Dr Eva Steliarova-Foucher

111

Meetings and Seminars

25/01/2006 The importance of the coding and classification of malignant haematological neoplasms in improving the incidence and mortality comparability of these tumours: Dr Carmen Martos 22/02/2006 Understanding the role of DNA repair molecules in tumorigenesis: Dr Wei-Min Tong 22/02/2006 Prediction of Prognosis of Prostate Cancer: Dr Lars Egevad 24/02/2006 Differentiating diffuse gliomas by their multi-chromosomal gene expression patterns: a new method of microarray data analysis: Dr Manuel Deprez 28/02/2006 Breast cancer incidence and mortality: Reasons for diverging time-trends: Dr Philippe Autier 06/03/2006 Lifestyle factors and cancer risk: Findings from a Japanese longitudinal study: Dr Catherine Sauvaget 06/03/2006 Screening in low-resource settings: With emphasis on study design, analysis and cost effectiveness: Mr Richard Muwonge 27/03/2006 Development of p53 peptide-based vaccines for immunotherapy of cancer: Dr Albert De Leo 10/04/2006 Cancer mortality trends in the European Union: priorities for cancer control: Dr Eva Negri 10/04/2006 Racial disparities in breast cancer mortality: why do postmenopausal African-American women not equally benefit from overall mortality decline? Dr Jerzy Tyczynski 10/04/2006 Can Mendelian randomization be used to 112

deconfound observational associations: Dr Nicholas Timpson 10/05/2006 The contribution of chromosomal instability to malignant transformation and drug resistance in breast cancer: Dr Carlos Galmarini 10/05/2006 Epigenetics and cancer: new developments and opportunities: Dr Zdenko Herceg 11/05/2006 Coffee and cancer, with a focus on liver cancer: Dr Carlo La Vecchia 22/05/2006 Cellular and Biochemical Characterization of tRNase Z, product of a candidate prostate cancer susceptibility gene: Dr Louis Levinger 22/05/2006 Mechanisms of carcinogenesis: relevance to cancer hazard evaluation: Dr Fatiha El Ghissassi 22/05/2006 Evaluating carcinogens: examples from the IARC Monographs: Dr Beatrice Secretan 07/07/2006 Recent advances in genomewide association studies: Dr John Witte 14/09/2006 Population based biomarker discovery for COPD progression: Ms Amelie Plymoth 14/09/2006 Measurement of endogenous sex steroids in post-menopausal women: application to large-scale epidemiological studies: Dr Sabina Rinaldi 15/09/2006 An overview of Diet and Cancer in California Seventh-day Adventists and a Short Critique of Measurement Error Issues in Dietary Research: Dr Gary Fraser 18/09/2006 Statistical approaches for the analysis of cancer genomics data in clinical research: Dr Philippe Broët

21/09/2006 Applying record-linkage methods to study risks of cancers in people with HIV/AIDS in developing countries: the case of the Uganda HIV/AIDS Cancer Match Study: Dr Sam Mbulaiteye 09/10/2006 In-treatment prevention models for ovarian hyperstimulation syndrome in controlled ovarian hyperstimulation using neural network: Dr Dai Imamura 09/10/2006 Treatment of local breast cancer and the role of the distance to radiation therapy facilities: Dr Lydia Voti 20/10/2006 A Bayesian model to correct for measurement error the diet/disease relationship in a multi-centric study: the experience of the EPIC study: Dr Pietro Ferrari 23/10/2006 The glycemic index: an update of the scientific evidence: Pr Jennie Brand-Miller 15/01/2007 Cancer Registration and Networking: Dr Hai-Rim Shin 15/01/2007 Cancer Registration: Challenge medium and low resources countries: Dr Maria Paula Curado

in

17/01/2007 Chromosomes and oncogenic Aurora kinases: from structure to mitotic functions: Dr Stefan Dimitrov 18/01/2007 Transformation of primary keratinocytes from different sites with mucosal human papillomaviruses and altered clinical HPV isolates from cancer: Dr Lubomir P. Turek 24/01/2007 Key role of IARC in descriptive cancer epidemiology: Dr Eva Steliarova-Foucher 09/02/2007 Flaxseed, Lignans and Breast Cancer: Dr Lilian Thompson

Meetings and Seminars

13/02/2007 Overall structure, calls and implementation of the EU 7th Framework Programme for Research & Development (FP7): Mr Markus Pasterk 13/02/2007 Somatic mutations of the protein kinase gene family in human cancers: Dr Christopher Hunter 13/02/2007 Application of genomics in farm animal breeding: Dr Dominique Rocha 14/02/2007 Smoking and cancer in the Million Women Study: Dr Valerie Beral 14/02/2007 Gene Variations Databases: lessons and perspectives from IARC TP53 Database: Dr Magali Olivier 14/02/2007 Identification of high-risk genes for psoriasis: Dr Fabienne Lesueur 05/03/2007 Structural basis for understanding oncogenic p53 mutations and designing rescue drugs: Dr Andreas Joerger 12/03/2007 Funding opportunities in the Seventh Framework Programme (FP7) in cancer research: Dr Olaf Kelm 13/03/2007 Funding opportunities in the Seventh Framework Programme (FP7) in cancer research: Dr Philippe Barruel 21/03/2007 Verbal Autopsy: Dr Nadia Soleman 22/03/2007 Dietary and Lifestyle Factors and Risk of Gastric Cancer. The EPIC-EurGast Study: Dr Mazda Jenab 22/03/2007 Detecting Pathway-Based Gene-Gene and Gene-Environment Interactions in

Pancreatic Cancer: Dr Eric Duell 02/04/2007 Multiplexed qPCR Assays Made Easy: Plexor™ Real-Time Quantitative PCR System: Dr Ilgar Abbaszade 25/04/2007 Imputation Methods for Adjusting for Covariate Measurement Error: Dr Victor Kipnis 27/04/2007 Getting more out of routinely collected cancer data: Dr Marco Martuzzi 27/04/2007 Descriptive epidemiology and screening on cancer: Dr Hai-Rim Shin 16/05/2007 Polymorphisms in DNA repair genes, ionizing radiation exposure and risk of breast cancer in U.S. Radiologic Technologists: Dr Parveen Bhatti 11/06/2007 Cancer registries supporting research: Dr Lydia Voti

cancer

19/06/2007 Identifying genes that cause lung cancer: Results from linkage studies and plans for genomewide association studies: Dr Chris Amos 22/06/2007 The analysis of mortality in the ELCAP study: Prof Claudia Henschke 22/06/2007 Evaluation of screening: Dr Olli Miettinen 26/06/2007 Estimating proportions of cancers attributable to lifestyle and environment in Europe: opportunities and methodological issues: Dr Mathieu Boniol 27/06/2007 Can we classify the 3-dimensional SAR distributions emitted by mobile phones? Dr Isabelle Deltour

27/06/2007 Familial aggregation and genetic epidemiology of cancer: Dr Justo Lorenzo Bermejo 01/10/2007 Efficient tests of Hardy Weinberg Equilibrium in genetic studies of siblings: Dr Graham Byrnes 01/10/2007 Detecting disease associated SNPs in genome wide association studies: Dr Ruth Pfeiffer 11/10/2007 The epidemiology of esophageal adenocarcinoma: is there a role for Helicobacter pylori: Dr Catherine de Martel 12/10/2007 Molecular markers of cancer risk in the Melbourne Collaborative Cohort Study: Dr Gianluca Severi 16/10/2007 The new IARC Grants Office (IGO) and the Research Project Life Cycle: Dr Olaf Kelm 14/11/2007 Risk factors for HPV prevalence and concurrent infection with multiple HPV types: pooled analyses of the IARC Multicentric HPV Prevalence Survey: Dr Salvatore Vaccarella 07/12/2007 The potential of international cancer screening networks to improve cancer control: lessons from the European experience: Dr L. Von Karsa Szentkiralyszabadja 10/12/2007 Bayesian intensity function estimation: a useful tool for descriptive epidemiology: Dr Jari Haukka 12/12/2007 Genome-wide association studies of prostate and breast cancer: the NCI CGEMS study: Dr Gilles Thomas

113

Staff Publications Accardi R, Dong W, Smet A, Cui R, Hautefeuille A, Gabet AS, Sylla BS, Gissmann L, Hainaut P, Tommasino M (2006). Skin human papillomavirus type 38 alters p53 functions by accumulation of deltaNp73. EMBO Rep 7(3):334-340. Achatz MI, Olivier M, Le Calvez F, MartelPlanche G, Lopes A, Rossi BM, Ashton-Prolla P, Vargas FR, Casali da Rocha JC, Vettore AL, Hainaut P (2007). Response to “Germline TP53 R337H mutation is not sufficient to establish Li-Fraumeni or Li-Fraumeni-like syndrome”, by Ribeiro et al. Cancer Lett 247(2):356-358. Achatz MI, Olivier M, Le Calvez F, MartelPlanche G, Lopes A, Rossi BM, Ashton-Prolla P, Giugliani R, Palmero EI, Vargas FR, Rocha JC, Vettore AL, Hainaut P (2007). The TP53 mutation, R337H, is associated with LiFraumeni and Li-Fraumeni-like syndromes in Brazilian families. Cancer Lett 245(1-2):96102. Agudo A, Sala N, Pera G, Capella G, Berenguer A, Garcia N, Palli D, Boeing H, Del GG, Saieva C, Carneiro F, Berrino F, Sacerdote C, Tumino R, Panico S, Berglund G, Siman H, Stenling R, Hallmans G, Martinez C, Bilbao R, Barricarte A, Navarro C, Quiros JR, Allen N, Key T, Bingham S, Khaw KT, Linseisen J, Nagel G, Overvad K, Tjonneland A, Olsen A, Buenode-Mesquita HB, Boshuizen HC, Peeters PH, Numans ME, Clavel-Chapelon F, BoutronRuault MC, Trichopoulou A, Lund E, Offerhaus J, Jenab M, Ferrari P, Norat T, Riboli E, Gonzalez CA (2006). Polymorphisms in metabolic genes related to tobacco smoke and the risk of gastric cancer in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev 15(12):2427-2434. Agudo A, Sala N, Pera G, Capella G, Berenguer A, Garcia N, Palli D, Boeing H, Del GG, Saieva C, Carneiro F, Berrino F, Sacerdote C, Tumino R, Panico S, Berglund G, Siman H, Stenling R, Hallmans G, Martinez C, Amiano P, Barricarte A, Navarro C, Quiros JR, Allen N, Key T, Bingham S, Khaw KT, Linseisen J, Nagel G, Overvad K, Tjonneland A, Olsen A, Buenode-Mesquita HB, Boshuizen HC, Peeters PH, Numans ME, Clavel-Chapelon F, Boutron114

Ruault MC, Trichopoulou A, Lund E, Blaker H, Jenab M, Ferrari P, Norat T, Riboli E, Gonzalez CA (2006). No association between polymorphisms in CYP2E1, GSTM1, NAT1, NAT2 and the risk of gastric adenocarcinoma in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev 15(5):1043-1045. Aguilar LV, Lazcano-Ponce E, Vaccarella S, Cruz A, Hernandez P, Smith JS, Munoz N, Kornegay JR, Hernandez-Avila M, Franceschi S (2006). Human papillomavirus in men: comparison of different genital sites. Sex Transm Infect 82(1):31-33. Ahlbom A, Feychting M, Cardis E, Elliott P (2007). Re: Cellular telephone use and cancer risk: update of a nationwide Danish cohort study. J Natl Cancer Inst 99(8):655-656. Akbari MR, Malekzadeh R, Nasrollahzadeh D, Amanian D, Sun P, Islami F, Sotoudeh M, Semnani S, Boffetta P, Dawsey SM, Ghadirian P, Narod SA (2006). Familial risks of esophageal cancer among the Turkmen population of the Caspian littoral of Iran. Int J Cancer 119(5):1047-1051. Al-Delaimy WK, Jansen EH, Peeters PH, van der Laan JD, van Noord PA, Boshuizen HC, van der Schouw YT, Jenab M, Ferrari P, Buenode-Mesquita HB (2006). Reliability of biomarkers of iron status, blood lipids, oxidative stress, vitamin D, C-reactive protein and fructosamine in two Dutch cohorts. Biomarkers 11(4):370-382. Al-Zoughool M, Talaska G (2006). 4Aminobiphenyl N-glucuronidation by liver microsomes: optimization of the reaction conditions and characterization of the UDPglucuronosyltransferase isoforms. J Appl Toxicol 26(6):524-532. Al-Zoughool M, Dossus L, Kaaks R, ClavelChapelon F, Tjonneland A, Olsen A, Overvad K, Boutron-Ruault MC, Gauthier E, Linseisen J, Chang-Claude J, Boeing H, Schulz M, Trichopoulou A, Chryssa T, Trichopoulos D, Berrino F, Palli D, Mattiello A, Tumino R, Sacerdote C, Bueno-de-Mesquita HB, Boshuizen HC, Peeters PH, Gram IT, Braaten T, Lund E, Chirlaque MD, Ardanaz E, Agudo A, Larranaga N, Quiros JR, Berglund G,

Manjer J, Lundin E, Hallmans G, Khaw KT, Bingham S, Allen N, Key T, Jenab M, Cust AE, Rinaldi S, Riboli E (2007). Risk of endometrial cancer in relationship to cigarette smoking: Results from the EPIC study. Int J Cancer 121(12):2741-2747. Algaba F, Mikuz G, Boccon-Gibod L, Trias I, Arce Y, Montironi R, Egevad L, Scarpelli M, Lopez-Beltran A (2007). Pseudoneoplastic lesions of the testis and paratesticular structures. Virchows Arch 451(6):987-997. Allen NE, Key TJ, Appleby PN, Travis RC, Roddam AW, Rinaldi S, Egevad L, Rohrmann S, Linseisen J, Pischon T, Boeing H, Johnsen NF, Tjonneland A, Gronbaek H, Overvad K, Kiemeney L, Bueno-de-Mesquita HB, Bingham S, Khaw KT, Tumino R, Berrino F, Mattiello A, Sacerdote C, Palli D, Quiros JR, Ardanaz E, Navarro C, Larranaga N, Gonzalez C, Sanchez MJ, Trichopoulou A, Travezea C, Trichopoulos D, Jenab M, Ferrari P, Riboli E, Kaaks R (2007). Serum insulin-like growth factor (IGF)-I and IGF-binding protein-3 concentrations and prostate cancer risk: results from the European Prospective Investigation into Cancer and Nutrition. Cancer Epidemiol Biomarkers Prev 16(6):1121-1127. Alsop K, Mead L, Smith LD, Royce SG, Tesoriero AA, Young JP, Haydon A, Grubb G, Giles GG, Jenkins MA, Hopper JL, Southey MC (2006). Low somatic K-ras mutation frequency in colorectal cancer diagnosed under the age of 45 years. Eur J Cancer 42(10):13571361. Andrieu N, Easton DF, Chang-Claude J, Rookus MA, Brohet R, Cardis E, Antoniou AC, Wagner T, Simard J, Evans G, Peock S, Fricker JP, Nogues C, Van’t VL, van Leeuwen FE, Goldgar DE (2006). Effect of chest Xrays on the risk of breast cancer among BRCA1/2 mutation carriers in the international BRCA1/2 carrier cohort study: a report from the EMBRACE, GENEPSO, GEO-HEBON, and IBCCS Collaborators’ Group. J Clin Oncol 24(21):3361-3366. Andrieu N, Goldgar DE, Easton DF, Rookus M, Brohet R, Antoniou AC, Peock S, Evans G, Eccles D, Douglas F, EMBRACE, Nogues C, Gauthier-Villars M, Chompret A,

Staff Publications GENESPRO, van Leeuwen FE, Kluijt I, GEO-HEBON, Benitez J, Arver B, Olah E, IBCCS Collaborators Group, Chang-Claude J (2006). Pregnancies, breast-feeding, and breast cancer risk in the International BRCA1/2 Carrier Cohort Study (IBCCS). J Natl Cancer Inst 98(8):535-544. Appleby P, Beral V, Berrington de GA, Colin D, Franceschi S, Goodhill A, Green J, Peto J, Plummer M, Sweetland S (2007). Cervical cancer and hormonal contraceptives: collaborative reanalysis of individual data for 16,573 women with cervical cancer and 35,509 women without cervical cancer from 24 epidemiological studies. Lancet 370(9599): 1609-1621. Aranda M, Gonzalez-Nilo F, Riadi G, Diaz V, Perez J, Martel G, Hainaut P, Mimbacas A (2007). Loss of TP53-DNA interaction induced by p.C135R in lung cancer. Oncol Rep 18(5):1213-1217. Arbyn M, Primic-Zakeus M, Raifu A, Grce M, Paraskevaidis E, Diakomanolis E, Kesic V, Nicula F, Suteu O, von Karsa L (2007). The burden of cervical cancer in South-East Europe at the beginning of the 21st century. Collegium Antropologicum 31(Suppl 2):7-10. Arbyn M, Sasieni P, Meijer CJ, Clavel C, Koliopoulos G, Dillner J (2006). Chapter 9: Clinical applications of HPV testing: A summary of meta-analyses. Vaccine 24(Suppl 3):S78-S89. Arbyn M, Tulunay G, Ozgul N, Yalvac S, Verguts J, Poppe W, Sankaranarayanan R (2006). European Union support for a Turkish reproductive health project to assess alternative cervical cancer screening methods in Sanliurfa (rural south-east Turkey). Eur J Cancer Prev 15(6):552-553. Arbyn M, Autier P, Ferlay J (2007). Burden of cervical cancer in the 27 member states of the European Union: estimates for 2004. Ann Oncol 18(8):1423-1425. Arbyn M, Raifu AO, Autier P, Ferlay J (2007). Burden of cervical cancer in Europe: estimates for 2004. Ann Oncol 18(10):1708-1715. Arbyn M, Dillner J (2007). Review of current knowledge on HPV vaccination: an appendix to the European Guidelines for Quality Assurance in Cervical Cancer Screening. J Clin Virol 38(3):189-197. Arndt V, Lacour B, Steliarova-Foucher E, Spix C, Znaor A, Pastore G, Stiller C, Brenner H (2007). Up-to-date monitoring of childhood cancer long-term survival in Europe: tumours of the sympathetic nervous system, retinoblastoma, renal and bone tumours, and soft tissue sarcomas. Ann Oncol 18(10):1722-1733.

Arndt V, Kaatsch P, Steliarova-Foucher E, Peris-Bonet R, Brenner H (2007). Up-to-date monitoring of childhood cancer long-term survival in Europe: central nervous system tumours. Ann Oncol 18(10):1734-1742. Arrossi S, Matos E, Zengarini N, Roth B, Sankaranayananan R, Parkin M (2007). The socio-economic impact of cervical cancer on patients and their families in Argentina, and its influence on radiotherapy compliance. Results from a cross-sectional study. Gynecol Oncol 105(2):335-340. Asadurian Y, Kurilin H, Lichtig H, Jackman A, Gonen P, Tommasino M, Zehbe I, Sherman L (2007). Activities of human papillomavirus 16 E6 natural variants in human keratinocytes. J Med Virol 79(11):1751-1760. Ateenyi-Agaba C, Weiderpass E, Tommasino M, Smet A, Arslan A, Dai M, KatongoleMbidde E, Hainaut P, Snijders PJ, Franceschi S (2006). Papillomavirus infection in the conjunctiva of individuals with and without AIDS: An autopsy series from Uganda. Cancer Lett 239(1):98-102. Autier P, Boniol M, Hery C, Masuyer E, Ferlay J (2007). Cancer survival statistics should be viewed with caution. Lancet Oncol 8(12):10501052. Autier P, Gandini S (2007). Vitamin D supplementation and total mortality: a metaanalysis of randomized controlled trials. Arch Intern Med 167(16):1730-1737.

genicity of carbon black, titanium dioxide, and talc. Lancet Oncol 7(4):295-296. Baglietto L, Jenkins MA, Severi G, Giles GG, Bishop DT, Boyle P, Hopper JL (2006). Measures of familial aggregation depend on definition of family history: meta-analysis for colorectal cancer. J Clin Epidemiol 59(2):114124. Bahrami H, Sadatsafavi M, Pourshams A, Kamangar F, Nouraie M, Semnani S, Brennan P, Boffetta P, Malekzadeh R (2006). Obesity and Hypertension in an Iranian Cohort Study; Iranian Women Experience Higher Rates of Obesity and Hypertension Than American Women. BMC Public Health 6(1):158. Bamia C, Trichopoulos D, Ferrari P, Overvad K, Bjerregaard L, Tjonneland A, Halkjaer J, Clavel-Chapelon F, Kesse E, Boutron-Ruault MC, Boffetta P, Nagel G, Linseisen J, Boeing H, Hoffmann K, Kasapa C, Orfanou A, Travezea C, Slimani N, Norat T, Palli D, Pala V, Panico S, Tumino R, Sacerdote C, Bueno-deMesquita HB, Waijers PM, Peeters PH, van der Schouw YT, Berenguer A, Martinez-Garcia C, Navarro C, Barricarte A, Dorronsoro M, Berglund G, Wirfalt E, Johansson I, Johansson G, Bingham S, Khaw KT, Spencer EA, Key T, Riboli E, Trichopoulou A (2007). Dietary patterns and survival of older Europeans: The EPIC-Elderly Study (European Prospective Investigation into Cancer and Nutrition). Public Health Nutr 10(6):590-598.

Autier P, Boniol M, Dore JF (2007). Sunscreen use and increased duration of intentional sun exposure: Still a burning issue. Int J Cancer 121(1):2755-2759.

Bancel B, Esteve J, Souquet JC, Toyokuni S, Ohshima H, Pignatelli B (2006). Differences in oxidative stress dependence between gastric adenocarcinoma subtypes. World J Gastroenterol 12(7):1005-1012.

Avard D, Bridge P, Bucci LM, Chiquette J, Dorval M, Durocher F, Easton D, Godard B, Goldgar D, Knoppers BM, Laframboise R, Lesperance B, Plante M, Tavtigian SV, Vezina H, Wilson B, Simard J (2006). Partnering in oncogenetic research - The INHERIT BRCAs experience: opportunities and challenges. Fam Cancer 5(1):3-13.

Bardin-Mikolajczak A, Lissowska J, Zaridze D, Szeszenia-Dabrowska N, Rudnai P, Fabianova E, Mates D, Navratilova M, Bencko V, Janout V, Fevotte J, Fletcher T, ‘t Mannetje A, Brennan P, Boffetta P (2007). Occupation and risk of lung cancer in Central and Eastern Europe: the IARC multi-center case-control study. Cancer Causes Control 18(6):645-654.

Baan R, Straif K., Grosse Y, Secretan B, El Ghissassi F, Bouvard V, Altieri A, Cogliano V, WHO International Agency for Research on Cancer Monograph Working Group (2007). Carcinogenicity of alcoholic beverages. Lancet Oncol 8(4):292-293.

Basu P, Sarkar S, Mukherjee S, Ghoshal M, Mittal S, Biswas S, Mandal R, Sankaranarayanan R (2006). Women’s perceptions and social barriers determine compliance to cervical screening: Results from a population based study in India. Cancer Detect Prev 30(4):369-374.

Baan RA (2007). Carcinogenic hazards from inhaled carbon black, titanium dioxide, and talc not containing asbestos or asbestiform fibers: recent evaluations by an IARC Monographs Working Group. Inhal Toxicol 19(Suppl 1):213228. Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, Cogliano V (2006). Carcino-

Becker N, de Sanjose S, Nieters A, Maynadie M, Foretova L, Cocco PL, Staines A, Alvaro T, Vornanen M, Brennan P, Boffetta P (2007). Birth order, allergies and lymphoma risk: Results of the European collaborative research project Epilymph. Leuk Res 31(10):1365-1372.

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Staff Publications Bel Hadj Jrad B, Mahfoudh W, Bouaouina N, Gabbouj S, Gargouri J, Ben Ahmed S, Ltaief M, Jalbout M, Chouchane L (2006). A polymorphism in FAS gene promoter associated with increased risk of nasoparyngeal carcinoma and correlated with anti-nuclear autoantibodies induction. Cancer Lett 233(1):21-27. Benoit V, de Moraes E, Dar NA, Taranchon E, Bours V, Hautefeuille A, Taniere P, Chariot A, Scoazec JY, De Moura Gallo CV, Merville MP, Hainaut P (2006). Transcriptional activation of cyclooxygenase-2 by tumor suppressor p53 requires nuclear factor-kappaB. Oncogene 25(42):5708-5718. Bernstein JL, Teraoka S, Southey MC, Jenkins MA, Andrulis IL, Knight JA, John EM, Lapinski R, Wolitzer AL, Whittemore AS, West D, Seminara D, Olson ER, Spurdle AB, Chenevix-Trench G, Giles GG, Hopper JL, Concannon P (2006). Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.10666T>G (IVS10-6T>G) from the Breast Cancer Family Registry. Hum Mutat 27(11):1122-1128. Berrington de Gonzalez A, Spencer EA, Bueno-de-Mesquita HB, Roddam A, Stolzenberg-Solomon R, Halkjaer J, Tjonneland A, Overvad K, Clavel-Chapelon F, Boutron-Ruault MC, Boeing H, Pischon T, Linseisen J, Rohrmann S, Trichopoulou A, Benetou V, Papadimitriou A, Pala V, Palli D, Panico S, Tumino R, Vineis P, Boshuizen HC, Ocke MC, Peeters PH, Lund E, Gonzalez CA, Larranaga N, Martinez-Garcia C, Mendez M, Navarro C, Quiros JR, Tormo MJ, Hallmans G, Ye W, Bingham SA, Khaw KT, Allen N, Key TJ, Jenab M, Norat T, Ferrari P, Riboli E (2006). Anthropometry, physical activity, and the risk of pancreatic cancer in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomarkers Prev 15(5):879-885. Besson H, Brennan P, Becker N, de Sanjose S, Nieters A, Font R, Maynadie M, Foretova L, Cocco PL, Staines A, Vornanen M, Boffetta P (2006). Tobacco smoking, alcohol drinking and Hodgkin’s lymphoma: a European multi-centre case-control study (EPILYMPH). Br J Cancer 95(3):378-384. Besson H, Brennan P, Becker N, Nieters A, de Sanjose S., Font R, Maynadie M, Foretova L, Cocco PL, Staines A, Vornanen M, Boffetta P (2006). Tobacco smoking, alcohol drinking and non-Hodgkin’s lymphoma: A European multicenter case-control study (Epilymph). Int J Cancer 119(4):901-908. Besson H, Banks R, Boffetta P (2006). Cancer mortality among butchers: a 24-state death certificate study. J Occup Environ Med 48(3):289-293. 116

Bjerregaard BK, Raaschou-Nielsen O, Sorensen M, Frederiksen K, Tjonneland A, Rohrmann S, Linseisen J, Bergman MM, Boeing H, Sieri S, Palli D, Tumino R, Sacerdote C, Bueno-deMesquita HB, Buchner FL, Gram IT, Braaten T, Lund E, Hallmans G, Agren A, Riboli E (2006). The effect of occasional smoking on smoking-related cancers : In the European Prospective Investigation into Cancer and Nutrition (EPIC). Cancer Causes Control 17(10):1305-1309. Bjerregaard BK, Raaschou-Nielsen O, Sorensen M, Frederiksen K, Christensen J, Tjonneland A, Overvad K, Chapelon FC, Nagel G, ChangClaude J, Bergmann MM, Boeing H, Trichopoulos D, Trichopoulou A, Oikonomou E, Berrino F, Palli D, Tumino R, Vineis P, Panico S, Peeters PH, Bueno-de-Mesquita HB, Kiemeney L, Gram IT, Braaten T, Lund E, Gonzalez CA, Berglund G, Allen N, Roddam A, Bingham S, Riboli E (2006). Tobacco smoke and bladder cancer—in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 119(10):2412-2416. Bleiberg H, Autier P, Huet F, Schrauwen AM, Staquet E, Delaunoit T, Hendlisz A, Wyns C, Panzer JM, Caucheteur B, Eisendrath P, Grivegnee A (2006). Colorectal cancer (CRC) screening using sigmoidoscopy followed by colonoscopy: a feasibility and efficacy study on a cancer institute based population. Ann Oncol 17(8):1328-1332. Bleiberg H, Grivegnee A, Hendlisz A, Autier P (2006). [Screening colorectal cancer: the selection of patients at risk]. Revue médicale de Bruxelles 27(4):S221-S223. Boeing H, Dietrich T, Hoffmann K, Pischon T, Ferrari P, Lahmann PH, Boutron-Ruault MC, Clavel-Chapelon F, Allen N, Key T, Skeie G, Lund E, Olsen A, Tjonneland A, Overvad K, Jensen MK, Rohrmann S, Linseisen J, Trichopoulou A, Bamia C, Psaltopoulou T, Weinehall L, Johansson I, Sanchez MJ, Jakszyn P, Ardanaz E, Amiano P, Chirlaque MD, Quiros JR, Wirfalt E, Berglund G, Peeters PH, Van Gils CH, Bueno-de-Mesquita HB, Buchner FL, Berrino F, Palli D, Sacerdote C, Tumino R, Panico S, Bingham S, Khaw KT, Slimani N, Norat T, Jenab M, Riboli E (2006). Intake of fruits and vegetables and risk of cancer of the upper aero-digestive tract: the prospective EPIC-study. Cancer Causes Control 17(7):957-969. Boffetta P, Aagnes B., Weiderpass E, Andersen A (2006). Response to comments by Drs. Rutqvist, Lewin, Nilsson, Ramstrom, Rodu and Cole further to the publication of the manuscript “smokeless tobacco use and risk of cancer of the pancreas and other organs”. Int J Cancer 118(6):1586-1587.

Boffetta P (2006). Human cancer from environmental pollutants: The epidemiological evidence. Mutat Res Rev Genet Toxicol 608(2):157-162. Boffetta P, Clark S, Shen M, Gislefoss R, Peto R, Andersen A (2006). Serum cotinine level as predictor of lung cancer risk. Cancer Epidemiol Biomarkers Prev 15(6):1184-1188. Boffetta P, Hashibe M, La Vecchia C, Zatonski W, Rehm J (2006). The burden of cancer attributable to alcohol drinking. Int J Cancer 119(4):884-887. Boffetta P, Armstrong B, Linet M, Kasten C, Cozen W, Hartge P (2007). Consortia in cancer epidemiology: lessons from InterLymph. Cancer Epidemiol Biomarkers Prev 16(2):197199. Boffetta P, McLaughlin JK, La Vecchia C, Autier P, Boyle P (2007). ‘Environment’ in cancer causation and etiological fraction: limitations and ambiguities. Carcinogenesis 28(5):913-915. Boffetta P, Van der Hel O, Norppa H, Fabianova E, Fucic A, Gundy S, Lazutka J, Cebulska-Wasilewska A, Puskailerova D, Znaor A, Kelecsenyi Z, Kurtinaitis J, Rachtan J, Forni A, Vermeulen R, Bonassi S (2007). Chromosomal aberrations and cancer risk: results of a cohort study from Central Europe. Am J Epidemiol 165(1):36-43. Boffetta P (2007). Molecular cancer epidemiology: a tale of >3842 publications. Carcinogenesis 28(8):1621. Boffetta P (2007). Endotoxins in lung cancer prevention. J Natl Cancer Inst 99(5):339. Boffetta P (2007). Epidemiology of peritoneal mesothelioma: a review. Ann Oncol 18(6):985990. Boffetta P, de Vocht F (2007). Occupation and the risk of non-hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev 16(3):369-372. Boffetta P, Tarone RE, Blot WJ (2007). Survival in women after diagnosis of lung cancer. JAMA 297(2):153. Boffetta P (2007). [Transparency in the relationship between IARC and the petroleum industry]. Epidemiol Prev 31(4):170. Boffetta P, Hashibe M (2006). Alcohol and cancer. Lancet Oncol 7(2):149-156. Boffetta P, Castaing M, Brennan P (2006). A Geographic Correlation Study of the Incidence of Pancreatic and other Cancers in Whites. Eur J Epidemiol 21(1):39-46.

Staff Publications Bonadona V, Dussart-Moser S, Voirin N, Sinilnikova OM, Mignotte H, Mathevet P, Bremond A, Treilleux I, Martin A, Romestaing P, Raudrant D, Rudigoz RC, Lenoir GM, Lasset C (2007). Prognosis of early-onset breast cancer based on BRCA1/2 mutation status in a French population-based cohort and review. Breast Cancer Res Treat 101(2):233-245. Boniol M, Autier P, Dore JF (2007). Photoprotection. Lancet 370(9597):1481-1482. Boniol M, Armstrong BK, Dore JF (2006). Variation in incidence and fatality of melanoma by season of diagnosis in new South Wales, Australia. Cancer Epidemiol Biomarkers Prev 15(3):524-526. Boonstra JJ, van der Velden AW, Beerens EC, van Marion R, Morita-Fujimura Y, Matsui Y, Nishihira T, Tselepis C, Hainaut P, Lowe AW, Beverloo BH, van Dekken H, Tilanus HW, Dinjens WN (2007). Mistaken identity of widely used esophageal adenocarcinoma cell line TE-7. Cancer Res 67(17):7996-8001. Bosetti C, Negri E, Gallus S, Dal Maso L, Franceschi S, La Vecchia C (2006). Anthropometry and Multiple Myeloma. Epidemiology 17(3):340-341. Bosetti C, Scotti L, Negri E, Talamini R, Levi F, Franceschi S, Montella M, Giacosa A, La Vecchia C. (2006). Benign ovarian cysts and breast cancer risk. Int J Cancer 119(7):16791682. Bosetti C, Bravi F, Talamini R, Parpinel M, Gnagnarella P, Negri E, Montella M, Lagiou P, Franceschi S, La Vecchia C (2006). Flavonoids and prostate cancer risk: a study in Italy. Nutr Cancer 56(2):123-127. Bosetti C, Talamini R, Negri E, Franceschi S, Montella M, La Vecchia C (2006). Aspirin and the risk of prostate cancer. Eur J Cancer Prev 15(1):43-45. Bosetti C, Boffetta P, La Vecchia C (2007). Occupational exposures to polycyclic aromatic hydrocarbons, and respiratory and urinary tract cancers: a quantitative review to 2005. Ann Oncol 18(3):431-446. Bosetti C, Scotti L, Dal Maso L, Talamini R, Montella M, Negri E, Ramazzotti V, Franceschi S, La Vecchia C (2007). Micronutrients and the risk of renal cell cancer: A case-control study from Italy. Int J Cancer 120(4):892-896. Bosetti C, Rossi M, McLaughlin JK, Negri E, Talamini R, Lagiou P, Montella M, Ramazzotti V, Franceschi S, La Vecchia C (2007). Flavonoids and the risk of renal cell carcinoma. Cancer Epidemiol Biomarkers Prev 16(1):98101.

Bouville A, Likhtarev IA, Kovgan LN, Minenko VF, Shinkarev SM, Drozdovitch VV (2007). Radiation dosimetry for highly contaminated Belarusian, Russian and Ukrainian populations, and. for less contaminated populations in Europe. Health Phys 93(5):487-501. Boyle P (2007). Conspiracy theories of cancer [book review]. Lancet 370(9601):1751. Boyle P, Yasantha AM, Barrington R, Bartelink H, Bartsch G, Berns A, de VD, Dinshaw KA, Eggermont AM, Gray N, Kakizoe T, Singh KB, Kaslar M, Kerr DJ, Khayat D, Khuhaprema T, Kim IH, Martin-Moreno J, McVie G, Park JG, Philip T, Ringborg U, Rodger A, Seffrin JR, Semiglazov V, Soo KC, Sun YT, Thomas R, Tursz T, Veronesi U, Wiestler O, Yoo KY, Zatonski W, Zhao P (2006). Tobacco: deadly in any form or disguise. Lancet 367(9524):1710-1712. Boyle P (2006). The globalisation of cancer. Lancet 368(9536):629-630. Bradley J, Coffey P, Arrossi S, Agurto I, Bingham A, Dzuba I, Kleine AM, Lewis R, White SC (2006). Women’s perspectives on cervical screening and treatment in developing countries: experiences with new technologies and service delivery strategies. Women Health 43(3):103-121. Brambilla C, Chabanon C, Diab S, Lorimier P, Delattre O, Goddet J, Hainaut P, Houdet P, Fest T, Lazar W, Lidereau R, Maraninichi D (2006). Constitution d’une cohorte prospective de tumeur. Bull Cancer 93(no. spec.):S229S236. Brat DJ, Shehata BM, Castellano-Sanchez AA, Hawkins C, Yost RB, Greco C, Mazewski C, Janss A, Ohgaki H, Perry A (2007). Congenital glioblastoma: a clinicopathologic and genetic analysis. Brain Pathol 17(3):276281. Bravi F, Scotti L, Bosetti C, Talamini R, Negri E, Montella M, Franceschi S, La Vecchia C (2006). Self-reported history of hypercholesterolaemia and gallstones and the risk of prostate cancer. Ann Oncol 17(6):10141017. Bravi F, Bosetti C, Dal Maso L, Talamini R, Montella M, Negri E, Ramazzotti V, Franceschi S, La Vecchia C (2006). Macronutrients, fatty acids, cholesterol, and risk of benign prostatic hyperplasia. Urology 67(6):1205-1211. Bravi F, Bosetti C, Scotti L, Talamini R, Montella M, Ramazzotti V, Negri E, Franceschi S, La Vecchia C (2007). Food groups and renal cell carcinoma: A case-control study from Italy. Int J Cancer 120(3):681-685.

Bravi F, Bosetti C, Tavani A, Bagnardi V, Gallus S, Negri E, Franceschi S, La Vecchia C (2007). Coffee drinking and hepatocellular carcinoma risk: a meta-analysis. Hepatology 46(2):430435. Bravi F, Bosetti C, Dal Maso L, Talamini R, Montella M, Negri E, Ramazzotti V, Franceschi S, La Vecchia C (2006). Food groups and risk of benign prostatic hyperplasia. Urology 67(1):73-79. Bray F, Richiardi L, Ekbom A, Pukkala E, Cuninkova M, Moller H (2006). Trends in testicular cancer incidence and mortality in 22 European countries: continuing increases in incidence and declines in mortality. Int J Cancer 118(12):3099-3111. Bray F, Richiardi L, Ekbom A, Forman D, Pukkala E, Cuninkova M, Moller H (2006). Do testicular seminoma and nonseminoma share the same etiology? Evidence from an ageperiod-cohort analysis of incidence trends in eight European countries. Cancer Epidemiol Biomarkers Prev 15(4):652-658. Bray F, Ferlay J, Devesa SS, McGlynn KA, Moller H (2006). Interpreting the international trends in testicular seminoma and nonseminoma incidence. Nat Clin Pract Urol 3(10):532-543. Brem R, Cox DG, Chapot B, Moullan N, Romestaing P, Gerard JP, Pisani P, Hall J (2006). The XRCC1 -77T->C variant: haplotypes, breast cancer risk, response to radiotherapy and the cellular response to DNA damage. Carcinogenesis 27(12):2469-2474. Bremnes Y, Ursin G, Bjurstam N, Rinaldi S, Kaaks R, Gram IT (2007). Insulin-like growth factor and mammographic density in postmenopausal Norwegian women. Cancer Epidemiol Biomarkers Prev 16(1):57-62. Bremnes Y, Ursin G, Bjurstam N, Rinaldi S, Kaaks R, Gram IT (2007). Endogenous sex hormones, prolactin and mammographic density in postmenopausal Norwegian women. Int J Cancer 121(11):2506-2511. Brennan P, Crispo A, Zaridze D, SzeszeniaDabrowska N, Rudnai P, Lissowska J, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, Fletcher T, Boffetta P (2006). High cumulative risk of lung cancer death among smokers and nonsmokers in Central and Eastern Europe. Am J Epidemiol 164(12):12331241. Brennan P, McKay J, Moore L, Zaridze D, Mukeria A, Szeszenia-Dabrowska N, Lissowska J, Rudnai P, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, Chow WH, Rothman N, Chabrier A, Gaborieau V, Odefrey F, Southey M, Hashibe M, Hall J, Boffetta P, 117

Staff Publications Peto J, Peto R, Hung RJ (2007). Uncommon CHEK2 mis-sense variant and reduced risk of tobacco-related cancers: case control study. Hum Mol Genet 16(15):1794-1801. Brenner H, Steliarova-Foucher E, Arndt V (2007). Up-to-date monitoring of childhood cancer long-term survival in Europe: methodology and application to all forms of cancer combined. Ann Oncol 18(9):1561-1568. Brenner H, Coebergh JW, Parkin DM, Izarzugaza I, Clavel J, Arndt V, SteliarovaFoucher E (2007). Up-to-date monitoring of childhood cancer long-term survival in Europe: leukaemias and lymphomas. Ann Oncol 18(9):1569-1577. Brizio C, Galluccio M, Wait R, Torchetti EM, Bafunno V, Accardi R, Gianazza E, Indiveri C, Barile M (2006). Over-expression in Escherichia coli and characterization of two recombinant isoforms of human FAD synthetase. Biochem Biophys Res Commun 344(3):1008-1016. Brohet RM, Goldgar DE, Easton DF, Antoniou AC, Andrieu N, Chang-Claude J, Peock S, Eeles RA, Cook M, Chu C, Nogues C, Lasset C, Berthet P, Meijers-Heijboer H, Gerdes AM, Olsson H, Caldes T, van Leeuwen FE, Rookus MA (2007). Oral contraceptives and breast cancer risk in the international BRCA1/2 carrier cohort study: a report from EMBRACE, GENEPSO, GEO-HEBON, and the IBCCS Collaborating Group. J Clin Oncol 25(25):3831-3836. Burdon KP, McKay JD, Wirth MG, RussellEggit IM, Bhatti S, Ruddle JB, Dimasi D, Mackey DA, Craig JE (2006). The PITX3 gene in posterior polar congenital cataract in Australia. Mol Vis 12:367-371. Burstyn I, Kromhout H, Johansen C, Langard S, Kauppinen T, Shaham J, Ferro G, Boffetta P (2007). Bladder cancer incidence and exposure to polycyclic aromatic hydrocarbons among asphalt pavers. Occup Environ Med 64(8):520526. Campa D, Zienolddiny S, Lind H, Ryberg D, Skaug V, Canzian F, Haugen A (2007). Polymorphisms of dopamine receptor/ transporter genes and risk of non-small cell lung cancer. Lung Cancer 56(1):17-23. Campa D, Hashibe M, Zaridze D, SzeszeniaDabrowska N, Mates IN, Janout V, Holcatova I, Fabianova E, Gaborieau V, Hung RJ, Boffetta P, Brennan P, Canzian F (2007). Association of common polymorphisms in inflammatory genes with risk of developing cancers of the upper aerodigestive tract. Cancer Causes Control 18(4):449-455.

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Muirhead CR, Schubauer-Berigan M, Yoshimura T, Bermann F, Cowper G, Fix J, Hacker C, Heinmiller B, Marshall M, ThierryChef I, Utterback D, Ahn YO, Amoros E, Ashmore P, Auvinen A, Bae JM, Bernar J, Biau A, Combalot E, Deboodt P, Sacristan AD, Eklof M, Engels H, Engholm G, Gulis G, Habib RR, Holan K, Hyvonen H, Kerekes A, Kurtinaitis J, Malker H, Martuzzi M, Mastauskas A, Monnet A, Moser M, Pearce MS, Richardson DB, Rodriguez-Artalejo F, Rogel A, Tardy H, Telle-Lamberton M, Turai I, Usel M, Veress K (2007). The 15-Country Collaborative Study of Cancer Risk among Radiation Workers in the Nuclear Industry: Estimates of Radiation-Related Cancer Risks. Radiat Res 167(4):396-416.

Cao WH, Wang X, Frappart L, Rigal D, Wang ZQ, Shen Y, Tong WM (2007). Analysis of genetic variants of the poly(ADP-ribose) polymerase-1 gene in breast cancer in French patients. Mutat Res 632(1-2):20-28.

Cardis E (2007). Current status and epidemiological research needs for achieving a better understanding of the consequences of the Chernobyl accident. Health Phys 93(5):542-546.

Cardis E, Howe G, Ron E, Bebeshko V, Bogdanova T, Bouville A, Carr Z, Chumak V, Davis S, Demidchik Y, Drozdovitch V, Gentner N, Gudzenko N, Hatch M, Ivanov V, Jacob P, Kapitonova E, Kenigsberg Y, Kesminiene A, Kopecky KJ, Kryuchkov V, Loos A, Pinchera A, Reiners C, Repacholi M, Shibata Y, Shore RE, Thomas G, Tirmarche M, Yamashita S, Zvonova I (2006). Cancer consequences of the Chernobyl accident: 20 years on. J Radiol Prot 26(2):127-140. Cardis E, Krewski D, Boniol M, Drozdovitch V, Darby SC, Gilbert ES, Akiba S, Benichou J, Ferlay J, Gandini S, Hill C, Howe G, Kesminiene A, Moser M, Sanchez M, Storm H, Voisin L, Boyle P (2006). Estimates of the cancer burden in Europe from radioactive fallout from the Chernobyl accident. Int J Cancer 119(6):1224-1235. Cardis E, Richardson L, Deltour I, Armstrong B, Feychting M, Johansen C, Kilkenny M, McKinney P, Modan B, Sadetzki S, Schuz J, Swerdlow A, Vrijheid M, Auvinen A, Berg G, Blettner M, Bowman J, Brown J, Chetrit A, Christensen HC, Cook A, Hepworth S, Giles G, Hours M, Iavarone I, Jarus-Hakak A, Klaeboe L, Krewski D, Lagorio S, Lonn S, Mann S, McBride M, Muir K, Nadon L, Parent ME, Pearce N, Salminen T, Schoemaker M, Schlehofer B, Siemiatycki J, Taki M, Takebayashi T, Tynes T, van Tongeren M, Vecchia P, Wiart J, Woodward A, Yamaguchi N (2007). The INTERPHONE study: design, epidemiological methods, and description of the study population. Eur J Epidemiol 22(9):647-664. Cardis E, Vrijheid M, Blettner M, Gilbert E, Hakama M, Hill C, Howe G, Kaldor J,

Cardis E, Hall J, Tavtigian SV (2007). Identification of women with an increased risk of developing radiation-induced breast cancer. Breast Cancer Res 9(3):106. Cardis E (2007). Commentary: Low dose-rate exposures to ionizing radiation. Int J Epidemiol 36(5):1046-1047. Cardy AH, Little J, Kean-Cowdin R, Lijinsky W, Choi NW, Cordier S, Filippini G, Holly EA, Lubin F, McCredie M, Mueller BA, PerisBonet R, Arslan A, Preston-Martin S (2006). Maternal medication use and the risk of brain tumors in the offspring: the SEARCH international case-control study. Int J Cancer 118(5):1302-1308. Carel R, Olsson AC, Zaridze D, SzeszeniaDabrowska N, Rudnai P, Lissowska J, Fabianova E, Cassidy A, Mates D, Bencko V, Foretova L, Janout V, Fevotte J, Fletcher T, t’ Mannetje A, Brennan P, Boffetta P (2007). Occupational exposure to asbestos and manmade vitreous fibres and risk of lung cancer: a multicentre case-control study in Europe. Occup Environ Med 64(8):502-508. Carneiro F, Moutinho C, Pera G, Caldas C, Fenger C, Offerhaus J, Save V, Stenling R, Nesi G, Mahlke U, Blaker H, Torrado J, Roukos DH, Sabourin JC, Boeing H, Palli D, Bueno-deMesquita HB, Overvad K, Bingham S, Clavel-Chapelon F, Lund E, Trichopoulou A, Manjer J, Riboli E, Gonzalez CA (2007). Pathology findings and validation of gastric and esophageal cancer cases in a European cohort (EPIC/EUR-GAST). Scand J Gastroenterol 42(5):618-627. Casey R, Brennan P, Becker N, Boffetta P, Cocco P, Domingo-Domenech E, Foretova L,

Staff Publications Nieters A, Sanjose SD, Staines A, Vornanen M, Maynadie M (2006). Influence of familial cancer history on lymphoid neoplasms risk validated in the large European case-control study epilymph. Eur J Cancer 42(15):2570-2576. Cassidy A, ‘t Mannetje A, van Tongeren M., Field JK, Zaridze D, Szeszenia-Dabrowska N, Rudnai P, Lissowska J, Fabianova E, Mates D, Bencko V, Foretova L, Janout V, Fevotte J, Fletcher T, Brennan P, Boffetta P (2007). Occupational exposure to crystalline silica and risk of lung cancer: a multicenter case-control study in Europe. Epidemiology 18(1):36-43. Castellsagué X, Diaz M, de Sanjose S., Munoz N, Herrero R, Franceschi S, Snijders PJF, Meijer CJLM, Bosch FX (2006). The worldwide human paoillomavirus etiology of cervical adenocarcinoma and its cofactors: implications for screening and prevention. J Natl Cancer Inst 98(5):303-315. Chang-Claude J, Andrieu N, Rookus M, Brohet R, Antoniou AC, Peock S, Davidson R, Izatt L, Cole T, Nogues C, Luporsi E, Huiart L, Hoogerbrugge N, van Leeuwen FE, Osorio A, Eyfjord J, Radice P, Goldgar DE, Easton DF, Epidemiological Study of Familial Breast Cancer (EMBRACE), Gene Etude Prospective Sein Ovaire (GENEPSO), Genen Omgeving studie van de werkgroep Hereditiair Borstkanker Onderzoek Nederland (GEOHEBON), International BRCA1/2 Carrier Cohort Study (IBCCS) collaborators group (2007). Age at menarche and menopause and breast cancer risk in the International BRCA1/2 Carrier Cohort Study. Cancer Epidemiol Biomarkers Prev 16(4):740-746. Chao C, Zhang ZF, Berthiller J, Boffetta P, Hashibe M (2006). NAD(P)H:quinone oxidoreductase 1 (NQO1) Pro187Ser polymorphism and the risk of lung, bladder, and colorectal cancers: a meta-analysis. Cancer Epidemiol Biomarkers Prev 15(5):979-987. Chen YC, Kraft P, Bretsky P, Ketkar S, Hunter DJ, Albanes D, Altshuler D, Andriole G, Berg CD, Boeing H, Burtt N, Bueno-de-Mesquita B, Cann H, Canzian F, Chanock S, Dunning A, Feigelson HS, Freedman M, Gaziano JM, Giovannucci E, Sanchez MJ, Haiman CA, Hallmans G, Hayes RB, Henderson BE, Hirschhorn J, Kaaks R, Key TJ, Kolonel LN, Lemarchand L, Ma J, Overvad K, Palli D, Pharaoh P, Pike M, Riboli E, Rodriguez C, Setiawan VW, Stampfer M, Stram DO, Thomas G, Thun MJ, Travis RC, Virtamo J, Trichopouiou A, Wacholder S, Weinstein SJ (2007). Sequence variants of estrogen receptor beta and risk of prostate cancer in the national cancer institute breast and prostate cancer cohort consortium. Cancer Epidemiol Biomarkers Prev 16(10):1973-1981.

Chenevix-Trench G, Healey S, Lakhani S, Waring P, Cummings M, Brinkworth R, Deffenbaugh AM, Burbidge LA, Pruss D, Judkins T, Scholl T, Bekessy A, Marsh A, Lovelock P, Wong M, Tesoriero A, Renard H, Southey M, Hopper JL, Yannoukakos K, Brown M, Easton D, Tavtigian SV, Goldgar D, Spurdle AB (2006). Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance. Cancer Res 66(4):20192027. Chiaffarino F, Parazzini F, Bosetti C, Franceschi S, Talamini R, Canzonieri V, Montella M, Ramazzotti V, Franceschi S, La Vecchia C (2007). Risk factors for ovarian cancer histotypes. Eur J Cancer 43(7):12081213. Chuang SC, Hashibe M, Yu GP, Le AD, Cao W, Hurwitz EL, Rao JY, Neugut AI, Zhang ZF (2006). Radiotherapy for primary thyroid cancer as a risk factor for second primary cancers. Cancer Lett 238(1):42-52. Chuang SC, Chen W, Hashibe M, Li G, Zhang ZF (2006). Survival rates of invasive breast cancer among ethnic Chinese women born in East Asia and the United States. Asian Pac J Cancer Prev 7(2):221-226. Clavel J, Steliarova-Foucher E, Berger C, Danon S, Valerianova Z (2006). Hodgkin’s disease incidence and survival in European children and adolescents (1978-1997): Report from the Automated Cancer Information System project. Eur J Cancer 42(13):20372049. Clifford G, Franceschi S, Diaz M, Munoz N, Villa LL (2006). Chapter 3: HPV typedistribution in women with and without cervical neoplastic diseases. Vaccine 24(Suppl 3):S26-S34. Clifford G, Franceschi S (2007). Immunity, infection, and cancer. Lancet 370(9581):6-7. Clifford GM, Goncalves MA, Franceschi S (2006). Human papillomavirus types among women infected with HIV: a meta-analysis. AIDS 20(18):2337-2344. Clifford GM, Shin HR, Oh JK, Waterboer T, Ju YH, Vaccarella S, Quint W, Pawlita M, Franceschi S (2007). Serologic response to oncogenic human papillomavirus types in male and female university students in busan, South Korea. Cancer Epidemiol Biomarkers Prev 16(9):1874-1879. Coebergh JW, Reedijk AM, de VE, Martos C, Jakab Z, Steliarova-Foucher E, Kamps WA (2006). Leukaemia incidence and survival in children and adolescents in Europe during

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Staff Publications De Andrea M, Gioia D, Mondini M, Azzimonti B, Reno F, Pecorari G, Landolfo V, Tommasino M, Accardi R, Herold-Mende C, Landolfo S, Gariglio M (2007). Effects of IFI16 overexpression on the growth and doxorubicin sensitivity of head and neck squamous cell carcinoma-derived cell lines. Head Neck 29(9):835-844. de Moraes E, Dar NA, De Moura Gallo CV, Hainaut P (2007). Cross-talks between cyclooxygenase-2 and tumor suppressor protein p53: Balancing life and death during inflammatory stress and carcinogenesis. Int J Cancer 121(5):929-937. de Sanjose S, Benavente Y, Nieters A, Foretova L, Maynadie M, Cocco PL, Staines A, Vornanen M, Boffetta P, Becker N, Alvaro T, Brennan P (2006). Association between Personal Use of Hair Dyes and Lymphoid Neoplasms in Europe. Am J Epidemiol 164(1):47-55. de Sanjose S, Diaz M, Castellsague X, Clifford G, Bruni L, Munoz N, Bosch FX (2007). Worldwide prevalence and genotype distribution of cervical human papillomavirus DNA in women with normal cytology: a metaanalysis. Lancet Infect Dis 7(7):453-459. de Sanjosé S, Bosch R, Schouten T, Verkuijlen S, Nieters A, Foretova L, Maynadie M, Cocco PL, Staines A, Becker N, Brennan P, Benavente Y, Boffetta P, Meijer CJ, Middeldorp JM (2007). Epstein-Barr virus infection and risk of lymphoma: Immunoblot analysis of antibody responses against EBV-related proteins in a large series of lymphoma subjects and matched controls. Int J Cancer 121(8):1806-1812. de Souza V, Sumita LM, Nascimento MC, Oliveira J, Mascheretti M, Quiroga M, Freire WS, Tateno A, Boulos M, Mayaud P, Pannuti CS (2007). Human herpesvirus-8 infection and oral shedding in Amerindian and nonAmerindian populations in the Brazilian Amazon region. J Infect Dis 196(6):844-852. De Stefani E., Ronco AL, Boffetta P, DeneoPellegrini H, Acosta G, Correa P, Mendilaharsu M (2006). Nutrient intake and risk of squamous cell carcinoma of the esophagus: a case-control study in Uruguay. Nutr Cancer 56(2):149-157.

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Dikshit RP, Ramadas K, Hashibe M, Thomas G, Somanathan T, Sankaranarayanan R (2006). Association between diabetes mellitus and premalignant oral diseases: A cross sectional study in Kerala, India. Int J Cancer 118(2):453-457. Dikshit RP, Gillio-Tos A, Brennan P, De Marco L, Fiano V, Martinez-Penuela JM, Boffetta P, Merletti F (2007). Hypermethylation, risk factors, clinical characteristics, and survival in 235 patients with laryngeal and hypopharyngeal cancers. Cancer 110(8):17451751. Dillner J, Arbyn M, Dillner L (2007). Translational mini-review series on vaccines: Monitoring of human papillomavirus vaccination. Clin Exp Immunol 148(2):199207.

de Vocht F, Burstyn I, Straif K, Vermeulen R, Jakobsson K, Nichols L, Peplonska B, Taeger D, Kromhout H (2007). Occupational exposure to NDMA and NMor in the European rubber industry. J Environ Monit 9(3):253-259.

Dossus L, Canzian F, Kaaks R, Boumertit A, Weiderpass E (2006). No association between progesterone receptor gene +331G/A polymorphism and endometrial cancer. Cancer Epidemiol Biomarkers Prev 15(7):1415-1416.

de Vries E, Steliarova-Foucher E, Spatz A, Ardanaz E, Eggermont AM, Coebergh JW (2006). Skin cancer incidence and survival in European children and adolescents (19781997). Report from the Automated Childhood Cancer Information System project. Eur J Cancer 42(13):2170-2182.

Dresler C, Marks S (2006). The emerging human right to tobacco control. Hum Rights Quart 28(3):599-651.

De Vuyst H, Franceschi S (2007). Human papillomavirus vaccines in HIV-positive men and women. Curr Opin Oncol 19(5):470-475. Deandrea S, Bertuccio P, Chatenoud L, Franceschi S, Serraino D, La Vecchia C (2007). Reply to ‘Alcohol consumption and risk of Hodgkin’s lymphoma and multiple myeloma: a multicentre case-control study’ by Gorini et al. Ann Oncol 18(6):1119-1121. Dechaud H, Denuziere A, Rinaldi S, Bocquet J, Lejeune H, Pugeat M (2007). Age-associated discrepancy between measured and calculated bioavailable testosterone in men. Clin Chem 53(4):723-728.

De Stefani E, Boffetta P, Deneo-Pellegrini H, Correa P, Ronco AL, Brennan P, Ferro G, Acosta G, Mendilaharsu M (2007). Nonalcoholic beverages and risk of bladder cancer in Uruguay. BMC cancer 7(1):57.

DeLellis Henderson K, Rinaldi S, Kaaks R, Kolonel L, Henderson B, Le Marchand L (2007). Lifestyle and Dietary Correlates of Plasma Insulin-Like Growth Factor Binding Protein-1 (IGFBP-1), Leptin, and C-Peptide: The Multiethnic Cohort. Nutr Cancer 58(2):136-145.

De Stefani E, Boffetta P, Deneo-Pellegrini H, Ronco AL, Acosta G, Ferro G, Oreggia F, Leiva J (2007). The effect of smoking and drinking in oral and pharyngeal cancers: A

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Staff Publications Gray N (2006). The consequences of the unregulated cigarette. Tob Control 15(5):405-408. Gray N (2006). The need for tobacco regulation. Tob Control 15(3):145. Grodzki M, Besson G, Clavel C, Arslan A, Franceschi S, Birembaut P, Tommasino M, Zehbe I (2006). Increased risk for cervical disease progression of French women infected with the human papillomavirus type 16 E6350G variant. Cancer Epidemiol Biomarkers Prev 15(4):820-822. Grosse Y, Baan R, Straif K, Secretan B, El GF, Cogliano V (2006). Carcinogenicity of nitrate, nitrite, and cyanobacterial peptide toxins. Lancet Oncol 7(8):628-629. Grosse Y, Baan R, Straif K, Secretan B, El GF, Bouvard V, Altieri A, Cogliano V (2007). Carcinogenicity of 1,3-butadiene, ethylene oxide, vinyl chloride, vinyl fluoride, and vinyl bromide. Lancet Oncol 8(8):679-680. Guarrera S, Sacerdote C, Fiorini L, Marsala R, Polidoro S, Gamberini S, Saletta F, Malaveille C, Talaska G, Vineis P, Matullo G (2007). Expression of DNA repair and metabolic genes in response to a flavonoid-rich diet. Br J Nutr 98(3):525-533. Guha N, Boffetta P, Wunsch F, V, Eluf NJ, Shangina O, Zaridze D, Curado MP, Koifman S, Matos E, Menezes A, Szeszenia-Dabrowska N, Fernandez L, Mates D, Daudt AW, Lissowska J, Dikshit R, Brennan P (2007). Oral health and risk of squamous cell carcinoma of the head and neck and esophagus: results of two multicentric case-control studies. Am J Epidemiol 166(10):1159-1173. Gunter MJ, Canzian F, Landi S, Chanock SJ, Sinha R, Rothman N (2006). Inflammationrelated gene polymorphisms and colorectal adenoma. Cancer Epidemiol Biomarkers Prev 15(6):1126-1131. Haentjens P, Autier P, Barette M, Venken K, Vanderschueren D, Boonen S (2007). Survival and functional outcome according to hip fracture type: A one-year prospective cohort study in elderly women with an intertrochanteric or femoral neck fracture. Bone 41(6):958-964. Haile RW, Thomas DC, McGuire V, Felberg A, John EM, Milne RL, Hopper JL, Jenkins MA, Levine AJ, Daly MM, Buys SS, Senie RT, Andrulis IL, Knight JA, Godwin AK, Southey M, McCredie MR, Giles GG, Andrews L, Tucker K, Miron A, Apicella C, Tesoriero A, Bane A, Pike MC, Whittemore AS (2006). BRCA1 and BRCA2 Mutation Carriers, Oral Contraceptive Use, and Breast Cancer Before Age 50. Cancer Epidemiol Biomarkers Prev 15(10):1863-1870.

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Vrijheid M, Cardis E, Ashmore P, Auvinen A, Bae JM, Engels H, Gilbert E, Gulis G, Habib R, Howe G, Kurtinaitis J, Malker H, Muirhead

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Staff Publications Weikert S, Boeing H, Pischon T, Olsen A, Tjonneland A, Overvad K, Becker N, Linseisen J, Lahmann PH, Arvaniti A, Kassapa C, Trichoupoulou A, Sieri S, Palli D, Tumino R, Vineis P, Panico S, Van Gils CH, Peeters PH, Bueno-de-Mesquita HB, Buchner FL, Ljungberg B, Hallmans G, Berglund G, Wirfalt E, Pera G, Dorronsoro M, Gurrea AB, Navarro C, Martinez C, Quiros JR, Allen N, Roddam A, Bingham S, Jenab M, Slimani N, Norat T, Riboli E (2006). Fruits and vegetables and renal cell carcinoma: findings from the European prospective investigation into cancer and nutrition (EPIC). Int J Cancer 118(12):3133-3139. Weiler M, Bahr O, Hohlweg U, Naumann U, Rieger J, Huang H, Tabatabai G, Krell HW, Ohgaki H, Weller M, Wick W (2006). BCLx(L): time-dependent dissociation between modulation of apoptosis and invasiveness in human malignant glioma cells. Cell Death Differ 13(7):1156-1169. Weiss JM, Huang WY, Rinaldi S, Fears TR, Chatterjee N, Chia D, Crawford ED, Kaaks R, Hayes RB (2007). IGF-1 and IGFBP-3: Risk of prostate cancer among men in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. Int J Cancer 121(10):22672273. Welch AA, Bingham SA, Ive J, Friesen MD, Wareham NJ, Riboli E, Khaw KT (2006). Dietary fish intake and plasma phospholipid n3 polyunsaturated fatty acid concentrations in men and women in the European Prospective Investigation into Cancer-Norfolk United Kingdom cohort. Am J Clin Nutr 84(6):13301339. Wellmann J, Weiland SK, Neiteler G, Klein G, Straif K. (2006). Cancer mortality in German carbon black workers 1976-1998. Occup Environ Med 63(8):513-521. Wiren S, Stocks T, Rinaldi S, Hallmans G, Bergh A, Stenman UH, Kaaks R, Stattin P (2007). Androgens and prostate cancer risk: A prospective study. Prostate 67(11):1230-1237. Wright TC, Blumenthal P, Bradley J, Denny L, Esmy PO, Jayant K, Nene BM, Pollack AE, Rajkumar R, Sankaranarayanan R, Sellors JW,

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Shastri SS, Sherris J, Tsu V (2007). Cervical cancer prevention for all the world’s women: New approaches offer opportunities and promise. Diagn Cytopathol 35(12):845-848. Wu RF, Dai M, Qiao YL, Clifford GM, Liu ZH, Arslan A, Li N, Shi JF, Snijders PJ, Meijer CJ, Franceschi S (2007). Human papillomavirus infection in women in Shenzhen City, People’s Republic of China, a population typical of recent Chinese urbanisation. Int J Cancer 121(6):1306-1311. Yang YG, Saidi A, Frappart PO, Min W, Barrucand C, Dumon-Jones V, Michelon J, Herceg Z, Wang ZQ (2006). Conditional deletion of Nbs1 in murine cells reveals its role in branching repair pathways of DNA doublestrand breaks. EMBO J 25(23):5527-5538. Yang YG, Frappart PO, Frappart L, Wang ZQ, Tong WM (2006). A novel function of DNA repair molecule Nbs1 in terminal differentiation of the lens fibre cells and cataractogenesis. DNA Repair (Amst) 5(8):885-893. Yin L, Puliti A, Bonora E, Evangelisti C, Conti V, Tong WM, Medard JJ, Lavoue MF, Forey N, Wang LC, Manie S, Morel G, Raccurt M, Wang ZQ, Romeo G (2007). C620R mutation of the murine ret proto-oncogene: loss of function effect in homozygotes and possible gain of function effect in heterozygotes. Int J Cancer 121(2):292-300. Yuille M, Van Ommen G-J, Brechot C, Cambon-Thomsen A, Dagher G, Landegren U, Littton J-E, Pasterk M, Peltonen L, Taussig M, Wichmann H-E, Zatloukal K (2007). Biobanking for Europe. Brief Bioinform Oct. 23; [Epub ahead of print]. Zatonski W, Mikucka M, La Vecchia C, Boyle P (2006). Infant mortality in Central Europe: effects of transition. Gac Sanit 20(1):63-66. Zeka A, ‘t Mannetje A, Zaridze D, SzeszeniaDabrowska N, Rudnai P, Lissowska J, Fabianova E, Mates D, Bencko V, Navratilova M, Cassidy A, Janout V, Travier N, Fevotte J, Fletcher T, Brennan P, Boffetta P (2006). Lung cancer and occupation in nonsmokers: A multicenter case-control study in Europe. Epidemiology 17(6):615-623.

Zeleniuch-Jacquotte A, Lundin E, Micheli A, Koenig KL, Lenner P, Muti P, Shore RE, Johansson I, Krogh V, Lukanova A, Stattin P, Afanasyeva Y, Rinaldi S, Arslan AA, Kaaks R, Berrino F, Hallmans G, Toniolo P, Adlercreutz H (2006). Circulating enterolactone and risk of endometrial cancer. Int J Cancer 119(10):2376-2381. Zhang Y, Holford TR, Leaderer B, Boyle P, Zhu Y, Wang R, Zou K, Zhang B, Wise JP, Qin Q, Kilfoy B, Han J, Zheng T (2007). Ultraviolet radiation exposure and risk of nonHodgkin’s lymphoma. Am J Epidemiol 165(11):1255-1264. Zhang Y, Wang R, Holford TR, Leaderer B, Zahm SH, Boyle P, Zhu Y, Qin Q, Zheng T (2007). Family history of hematopoietic and non-hematopoietic malignancies and risk of non-Hodgkin lymphoma. Cancer Causes Control 18(4):351-359. Zhu Y, Huang H, Tu Y (2006). A review of recent studies in China on the possible beneficial health effects of tea. Int J Food Sci Technol 41(4):333-340. Zhu Y, Leaderer D, Guss C, Brown HN, Zhang Y, Boyle P, Stevens RG, Hoffman A, Qin Q, Han X, Zheng T (2007). Ala394Thr polymorphism in the clock gene NPAS2: A circadian modifier for the risk of nonHodgkin’s lymphoma. Int J Cancer 120(2):432-435. Zhu Y, Zheng T, Stevens RG, Zhang Y, Boyle P (2006). Does “clock” matter in prostate cancer? Cancer Epidemiol Biomarkers Prev 15(1):3-5. Zienolddiny S, Campa D, Lind H, Ryberg D, Skaug V, Stangeland L, Phillips DH, Canzian F, Haugen A (2006). Polymorphisms of DNA repair genes and risk of non-small cell lung cancer. Carcinogenesis 27(3):560-567. Zucchetto A, Dal Maso L, Tavani A, Montella M, Ramazzotti V, Talamini R, Canzonieri V, Garbeglio A, Negri E, Franceschi S, La Vecchia C (2007). History of treated hypertension and diabetes mellitus and risk of renal cell cancer. Ann Oncol 18(3):596-600.

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