Advances in Cancer Research Volume 62

ADVANCES IN CANCER RESEARCH VOLUME 62

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ADVANCES IN CANCERRESEARCH Edited by

GEORGE F. VANDE WOUDE ABL-Basic Research Program NCI-Frederick Cancer Research and Development Center Frederick, Maryland

GEORGE KLEIN Department of Tumor Biology Karolinska lnstitutet Stockholm, Sweden

Volume 62 ACADEMIC PRESS, INC. A Division of liarcourt Brace 8 Company

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QW

9 8 1 6 5 4 3 2 1

CONTENTS

CONTKIBUTOKS TO VOLUME 62 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Foundations in Cancer Research-Chromosomes The Evolution of an Idea PETER

ix

and Cancer:

C. NOWELL

I . Introduction . . . .. ............ ............... .SO) . . . . . . . . ............... 11. Boveri and Early (B 111. The Sternline Concept and Modern Cytogenetics IV. Early Findings in the Pre-banding Era (the 1960s) . . . . . . . . . . . . . . . . . . . V. Chromosome Banding and Clonal Evolution (the 1970s) . . . . . . . . . . . . . V I . Molecular Cytogenetics (the 1980s) .................... V l I . Conclusions . , . .. ................................. References ...................... ....................

I 1 3 > * I

10 14

14

Pathways of Ras Function: Connections to the Actin Cytoskeleton

GEORGE C. PRENDERCAST AND

JACKSON

B. GIBBS

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Ras Guanine Nucleotide Exchange Factors . . . . . . . . . . . . . . . . . . . . . . . . . . 111. CAP and GAP-Associated Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

IV. Signal Transduction Pathways Dttwnstream of Ras . . . . . . . . . . . . . . . . . . . V. Perspectives on Ras Function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Note Added in P r o d . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

v

19

20 29 35 415

.52 64

vi

CONTENTS

The Role of the Adenomatous Polyposis Coli (APC) Gene in Human Cancers

YUSUKENAKAMURA I. Identification of the APC Gene . . . . . . , . , . , . . . . . . . . . . . . . . . . . . . . . . . . . 11. Germline Mutations of the APC Gene in Familial Adenomatous Polyposis Patients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111. Somatic Mutations of the APC Gene in Colorectal Tumors . . . . . . . . . . . IV. Somatic Mutations of the APC Gene in Other Human Cancers . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

65 66 74 80 83

Molecular Cytogenetics of Renal Cell Tumors

GYULAKOVACS I. Introduction . _ _ _ __ _. _ _ _ _ . . . . . . . . . . _ . ., . . . . _ _ . . . . . . . . . . . . . . . . . . . . . 11. Differential Genetics of Renal Cell Tumors . . . . . . . . . . . . . . . . . . . . . . . . . 111. Genetics of Nonpapillary Renal Cell Carcinomas . . . . . . . . . . . . . . . . . . . . IV. V. VI. VII.

Genetics of Papillary Renal Cell Tumors ...................... Renal Oncocytoma . . . . . . . ... ........... Chromophobe Renal Cell Carcinoma . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References .......................................................

89 90 91 105 115 117 118

119

Reverse Transformation, Genome Exposure, and Cancer

THEODORE T. PUCKAND ALPHONSE KRYSTOSEK I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Review of Reverse Transformation (Redifferentiation) . . . . . . . . . . . . . . . 111. T h e Genome Exposure Defect in Cancer

I V. V. VI. VII.

Restoration of Genome Exposure in Trans Differentiation Induction in Malignant Cells as Reverse T Relationship to Other Work on DNase I Sensitivity . . . . . . . . . . . . . . . . . . Theoretical Formulation about Signal Transduction Mechanisms Governing Genome Exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VIII. Further Unsolved Problems and Some Experimental Predictions of the ...................... Model . . . . . . . . . . . . . . . . . . ...................... IX. Therapeutic and Preventat

12.5 126 127

132 133 135

139 143 145

vii

CONTENTS

X. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

147 147

Peptide-Binding Heat Shock Proteins in the Endoplasmic Reticulum: Role in Immune Response to Cancer and in Antigen Presentation

PRAMOD K. SRIVASTAVA I. T h e Curious Paradox of Heat Shock Proteins as Tumor-Specific Antigens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Hypothesis That HSPs Chaperone Antigenic Peptides . . . . . . . . . . . . . . . 111. Evidence in Support of the Hypothesis ............................. IV. Mechanisms by Which HSPs Elicit Specific Immunity ................ V. Implications for Immunity to Cancer ............................... VI. Implications for Antigen Presentation .............................. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

154 160 160 167 167 172 175

The Association of Epstein-Barr Virus (EBV) with T Cell Lymphoproliferationsand Hodgkin’s Disease: Two New Developments in the EBV Field

GORMPALLESEN, STEPHEN J. HAMILTON-DUTOIT, AND XIAOCE Z H O U

I. 11. 111. IV. V.

Introduction ......... .................................. Biology of EBV . . . . . . .................... Detection of EBV Markers in Tissues . . . . . . . . . . . . . . . . EBV and T Cell Lymphoproliferations ............................. ........................ EBV and Hodgkin’s Disease . . . . . . . . . References ............................... ... ....

180

187 212 231

The Role of Direct Cellular Communication during the Development of a Humoral Immune Response

E. CHARLES SNOW

AND RANDOLPH

J. NOELLE

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Contributions of Lymphoid Tissue Architecture ..................... 111. Activation of T h Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

241 242 245

...

CONTENTS

Vlll

IV. V. VI. VII .

Activation of Naive B Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . TI1 Cell Regulation of Follicular B Cell Survival . . . . . . . . . . . . . . . . . . . . . T h Cell Regulation of B Cell Isotype Switching ...................... Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

246 256 2.59 260 261

INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

267

CONTRIBUTORS

Numbers in parentheses indicate the pages on which the authors’ contributions begin.

B. GIBBS,Department of Cancer Research, Merck Research Luboratories, West Point, Pennsylvania 19486 (19) STEPHEN J. HAMILTON-DUTOIT, Laboratory of Immunopathology, A a r h Uniuersity Hospital, DK-8000 Aarhus C, Denmark (179) GYULAKOVACS, National Cancer Center Research Institute, Tokyo, Japan (89) ALPHONSE K n Y s T o s E K , Eleanor Roosevelt Institute, Denver, Colorado 80206 (125) YUSUKENAKAMURA, Department of Biochemistry, Cancer Institute, Toshima, Tokyo 170, Japan (65) RANDOLPHJ. NOELLE, Department of MicrobioloRy, Dartmouth Medical School, Hanover, New Hampshire 03756 (241) PETER C. NOWELL, Department of Patholo\gy and Laboratory Medicine, University of Pennsyluaniu School of Medicine, P h i ~ ~ d e l p ~ Pennsyluuniu ~iu, 19104 (1) GORMPALLESEN, Laboratory of Immunopatholoo.o 1 >O.OlP 0.4310.57< 0.3410.66@ >O.OlC 0.9710.03e >O.Ol< 0.9810.02J >O.OlP >o.o 1p >O.Ol*

7 7 8 11 13 13 14 15 15 15 15 15 15 15 15

15 15 15 15 15 15 15 15 15

TyrITyr A 1aIA1a LeulLeu AsnlAsn ProlSer IlelIle Asnl Asp ThrIMet IleIVal LysILys Asp1Asp ThrIThr GlylGly ValIVal SerISer

AspIVal ProIPro LeulLeu GlyISer GlyIGly

Enzyme site

Rsa I

>0.01*

>O.Ol< >O.Ol? 0.3510.65* 0.6410.36p N.I. N.I. 0.9010.10f 0.6310.37f 0.01. 0.0 11' 0.9610.04f

Dsa I HgzAI

Estimated among 150 unrelated FAP patients. Miyoshi et al. (1992a). c Groden el al. (1991). r' Fodde et al. (1992). Nagase et al. (1992b). / Powell et al. (1992). N.1.. no information. 0

h

Ill. Somatic Mutations of the APC Gene in Colorectal Tumors

A. DETECTION OF SOMATIC MUTATIONS IN COLORECTAL TUMORS At this writing, 85 somatic mutations in 65 colorectal tumors (19 adenomas and 46 carcinomas) have been reported (Nishisho et al., 1991; Miyoshi et al., 1992b; Powell et al., 1992; Cottell et al., 1992) (Table V).

ROLE OF APC GENE IN HUMAN CANCERS

75

TABLE V TYPES OF 85 SOMATIC MUTATIONS IN THE APC Gene" Point mutations Nonsense mutation Missense mutation Splice site Frameshift mutations Deletion (1-31 bp) Insertion (1 bp) Total

40

32 3 5

45

35 10 85

0 43 mutations in 37 colorectal tumors (9 adenomas and 28 carcinomas) (Miyoshi ef al., 1992b); 35 mutations in 10 adenomas and 15 carcinomas (Powell et al., 1992); 7 mutations in 3 carcinomas and 4 cell lines (Cottrell el al., 1992).

Forty of these mutations were point mutations; 32 were nonsense, and three were missense. Five occurred in introns at or very close to intronexon junctions and would be considered to cause abnormal splicing; 45 were frameshift mutations due to 1- to 31-bp deletions or 1- to 4-bp insertions. As in the case of germline APC mutations, the great majority (82/85) of somatic mutations that have been identified in colorectal tumors are of a kind predicted to truncate the gene product. Although it is uncertain whether the three missense mutations (Ser to Tyr at codon 906, Glu to Gly at codon 911, and Thr to Ala at codon 1313) would significantly affect the biological function of the gene product, these mutations might point to functionally important domains of the APC protein. Figure 1B presents the distribution of 78 known APC gene mutations that have occurred somatically (Miyoshi et al., 1992b; Powell et al., 1992) (the data from two reports were used in this figure, since both groups examined the entire coding region of the APC gene). Although they are scattered through the 5' half of the APC gene, 46 (nearly 60%) are clustered within a very small part (less than 10%) of the coding region within the segment from codon 1286 to 1513, that has been designated MCR (mutation cluster region) (Miyoshi et al., 199213). T h e ratio of point versus frame shift mutations in APC between germline and somatic mutations is not same; 36% point mutations versus 64% frameshift mutations for germline mutations and 47% versus 53% for somatic mutations. Point mutations seemed slightly higher for somatic mutations than for germline mutations. This tendency may or

76

YUSUKE NAKAMURA

S U M M A R Y OF

TABLE V1 SOMATIC POINTMUTATIONSOF THE APC GENE I N COLORECTAL TUMORS

Frorn/to'

C

C T G A

Total c'

T

G

A

Total

-

19 -

1 0

5 0

25

1 0 0

-

1

4

-

5

6

1

7 2 28

1 8

6 40

Listed in coding strand

may not be general because the methods used and the regions examined have varied among research groups. However, data from our laboratory derived from 103 germline mutations and 43 somatic mutations have supported its generality. Nineteen of 40 point mutations found in colorectal tumors occurred at C residues (Table VI); most of these were at CpG sites (14 cases), in a ratio similar to that in germline mutations (13 CpG sites among 44 point mutations). However, the frequency of somatic APC point mutations at CpG sites in American patients (9 in 17 cases, 53%) was much higher than that seen in Japanese patients (5 in 21 cases, 24%). Since the incidence of colorectal carcinomas is much higher in the United States than in Japan, this difference in mutation frequency at CpG sites might reflect differences in dietary habits. B. DOESTHE FORMATION OF ADENOMAS REQUIRE TWO MUTATIONALHITSIN THE APC GENE? Although some reports have suggested that loss of the normal allele at the APC locus causes mild o r moderate adenomas to become more progressive (Bodmer et al., 1987), whether the initial step of adenoma formation is caused by decreased dosage or by the complete loss of the APC gene product is unclear. Data from two groups (Miyoshi et al., 1992b; Powell et al., 1992) have indicated that both copies of the APC gene are inactivated in the majority of colorectal tumors (both carcinomas and adenomas) due to point mutations, insertion or deletion of several nucleotides, or loss of the chromosomal segment spanning the APC locus. Table VII summarizes data reported by Miyoshi et al. (1992b). Of 47 carcinomas, 39 (83%) bare at least one mutation in APC and 23 had sustained two separate mutational events; 17 of these 23 cases were

77

ROLE OF APC GENE IN HUMAN CANCERS

MUTATIONSAT

THE

TABLE VII APC Locus OBSERVED I N GOLORECTAL TUMORS"

Carcinoma Type of mutation(s) detected

LOHh + somatic or germline mutation Two mutations (somatic and/or germline) LOHb One somatic mutation None Total (including 4 carcinomas developed in FAP patients) Adenoma Type of mutation(s) detected LOH* -t somatic or germline mutation Two mutations (somatic and/or germline) LOHh One somatic or germline mutation None Total (including 8 adenomas developed in FAP patients)

Number of tumors

15 8 10

6 8 47 Number of tumors

16

From Miyoshi el al. (1992b). Although LOH is in fact a somatic event, LOH was scored separately from specific mutations within the A P C gene. 0

h

confirmed to involve both alleles. Similar results were observed among 16 adenomas: 14 bare at least one inactivated APC allele, and in 9 of these, both copies were inactivated. T h e frequency of somatic mutations reflected in Table VII is likely to be an underestimate, because the RNase protection analysis does not detect all mismatches and because we did not examine introns or the 5' flanking region. Using the same method, we detected germline mutations in only 70% of FAP patients studied (Nagase et al., 1992b). Hence, it seems likely that mutations of the APC gene, probably on both alleles, are involved in the great majority of colorectal tumors. To further examine whether the dosage effect of germline mutations in patients with familial adenomatous polyposis is sufficient to cause colorectal adenomas or whether an additional somatic mutation of the normal allele is required as well (Knudson, 1985), we investigated somatic mutations of APC in adenomas removed from one FAP patient (Ichii et al., 1992). Taking advantage of a constitutional 5-bp (AAAGA) deletion detected in the region containing a tandemly repeated AAAAGAAAAGA around codon 1309, we examined allelic loss using

78

YUSUKE NAKAMURA

91

88