Genetic Predisposition to Cancer

423 Pages·1996·15.36 MB·English

by  Rosalind A. Eeles, Douglas F. Easton, Bruce A. J. Ponder, Alan Horwich (eds.)

Genetic Predisposition
to Cancer
Genetic Predisposition
to Cancer
Edited by
Rosalind A. Eeles
Senior Lecturer and Honorary Consultant in Cancer Genetics and
Clinical Oncology, Institute of Cancer Research and Royal Marsden
Hospital, Surrey, UK
Bruce A. J. Ponder
Director, CRC Human Cancer Genetics Research Group, University of
Cambridge, UK
Douglas F. Easton
Director, CRC Genetic Epidemiology Unit, University of Cambridge, UK
Alan Horwich
Director of Clinical Research, Academic Unit of Radiotherapy and Oncology,
Institute of Cancer Research and Royal Marsden Hospital, Surrey, UK
With a Foreword by
Gordon McVie
Cancer Research Campaign, London, UK
I~ I] I SPRINGER-SCIENCE+BUSINESS MEDIA, B.Y.
First edition 1996
© Springer Science+Business Media Dordrecht 1996
Originally published by Chapman & Hall in 1996
Softcover reprint of the hardcover 1st edition 1996
Typeset in 10/12 Palatino by Photoprint, Torquay, Devon
ISBN 978-0-412-56580-9 ISBN 978-1-4899-4501-3 (eBook)
DOI 10.1007/978-1-4899-4501-3
Apart from any fair dealing for the purposes of research or private
study, or criticism or review, as permitted under the UK Copyright
Designs and Patents Act. 1988, this publication may not be
reproduced, stored, or transmitted, in any form or by any means,
without the prior permission in writing of the publishers, or in the
case of reprographic reproduction only in accordance with the terms of
the licences issued by the Copyright Licensing Agency in the UK, or in
accordance with the terms of licences issued by the appropriate
Reproduction Rights Organization outside the UK. Enquiries
concerning reproduction outside the terms stated here should be sent
to the publishers at the London address printed on this page.
The publisher makes no representation, express or implied, with
regard to the accuracy of the information contained in this book and
cannot accept any legal responsibility or liability for any errors or
omissions that may be made.
A catalogue record for this book is available from the British Library
Library of Congress Catalog Card Number
(55) Printed on acid-free text paper, manufactured in accordance with
ANSI/NISO Z39, 4&-1992 (Permanence of Paper).
Contents
Colour plate section appears between pp. 340 and 341
Contributors xiii
Foreword xvii
Preface xix
Part One Basic Principles 1
1 Genetic predisposition to cancer: an introduction 3
D. Timothy Bishop
1.1 Introduction 3
1.2 Identifying genes associated with risk of cancer 8
1.3 Mechanism of action of predisposing genes 9
1.4 Colorectal cancer as an example 11
1.5 Summary 13
References 13
2 From families to chromosomes: genetic linkage, and other methods for
finding cancer-predisposition genes 16
Douglas F. Easton
2.1 Introduction 16
2.2 General principles of linkage analysis 17
2.3 Statistical analysis of linkage data 18
2.4 Example of LOD score calculations 20
2.5 Notes on LOD score calculations 22
2.6 Types of genetic marker and laboratory techniques 23
2.7 Multipoint linkage analysis 24
2.8 Genetic heterogeneity 26
2.9 Non-parametric methods of linkage analysis 28
2.10 Pitfalls in linkage analysis 29
2.11 Design considerations 30
2.12 Estimating penetrance 32
2.13 Predictive testing 32
2.14 Use of loss of heterozygosity data in tumours 33
2.15 Phenotypic markers 33
2.16 Association studies 34
v
Contents
2.17 Discussion 35
References 36
3 From chromosomes to genes: how to isolate cancer-predispostion genes 40
Helen Patterson and Colin Cooper
3.1 Introduction 40
3.2 Physical mapping techniques 40
3.3 Cloning strategies 44
3.4 Analysis of cloned DNA for candidate genes 45
3.5 Cloning of the retinoblastoma gene 47
3.6 Cloning of the Wilms tumour gene 49
3.7 Cloning of the neurofibromatosis type 1 gene 51
3.8 Familial adenomatous polyposis coli (APC) 51
3.9 Candidate genes 52
3.10 Conclusion 53
References 53
Part Two Inherited Cancer Syndromes 57
4 Retinoblastoma: the paradigm for a genetically inherited cancer syndrome 58
John K. Cowell
4.1 Introduction 58
4.2 Retinoblastoma (Rb) genetics 58
4.3 Defining the RB locus 60
4.4 Isolation of the RBI gene 60
4.5 Mutations in the RBI gene 61
4.6 Clinical applications in the identification of RBI 62
4.7 The function of the RBI gene 63
4.8 RBI mutations in other tumours 65
4.9 Suppression of the malignant phenotype 66
4.10 Transgenic mouse studies 67
4.11 Summary 67
References 68
5 Neurofibromatosis (NF) types 1 and 2 70
Susan M. Huson
5.1 Introduction 70
5.2 Neurofibromatosis type 1 (NFl) 72
5.3 Neurofibromatosis type 2 (NF2) 87
References 94
6 Multiple endocrine neoplasia 98
Bruce A.J. Ponder
6.1 Introduction 98
6.2 Multiple endocrine neoplasia type 1 (MEN 1) 98
6.3 Multiple endocrine neoplasia type 2 (MEN 2) 100
References 103
vi
Contents
7 Wilms tumour and other genetic causes of renal cancer 105
Kathryn Pritchard-Jones
7.1 Introduction 105
7.2 Renal tumours in childhood 105
7.3 Kidney tumours in adults 114
References 118
8 The Li-Fraumeni syndrome and the role of TP53 mutations in
predisposition to cancer 123
Jillian M. Birch
8.1 Introduction and definitions 123
8.2 Identification of TP53 as a cause of LFS 126
8.3 Germline TP53 mutations and sarcomas and leukaemias 127
8.4 Germline TP53 mutations and multiple tumours 128
8.5 Germline TP53 mutations and breast cancer 128
8.6 Distribution of germline mutations in TP53 129
8.7 Mutations outside the coding regions of the TP53 gene 130
8.8 Penetrance and phenotypic expression of TP53 130
8.9 LFS and LFS-like families not due to TP53 131
8.10 Predictive genetic testing 132
8.11 Conclusions 133
References 133
Part Three Chromosome Fragility Syndromes and the Godin Syndrome 137
9 Malignant disease and variations in radiosensitivity in ataxia
telangiectasia patients 138
A. Malcolm R. Taylor, D. Hernandez, CM. McConville, CC. Woods,
M. Stacey, P. Biggs, P.J. Byrd, CF. Arlett and D. Scott
9.1 Introduction 138
9.2 Malignant disease in ataxia telangiectasia 138
9.3 The A-T gene in the heterozygous state 139
9.4 Localization and isolation of the A-T gene 140
9.5 Clinical heterogeneity in ataxia telangiectasia 140
9.6 Low radiosensitivity variants of ataxia telangiectasia 141
9.7 Discussion 146
References 150
10 Fanconi's anaemia 152
Christopher C. Mathew
10.1 Clinical and laboratory diagnosis of Fanconi's anaemia 152
10.2 Genetics ofFanconi's anaemia 153
10.3 Cancer predisposition in Fanconi's anaemia 153
10.4 What is the basic defect? 154
10.5 Identification of the FA genes 155
vii
Contents
10.6 The FA Group C (FAC) gene 157
10.7 The future 160
References 161
11 The Godin (nevoid basal cell carcinoma) syndrome 164
Peter A. Farndon
11.1 The Godin syndrome 164
11.2 Features of the syndrome 165
11.3 Diagnosis and differential diagnosis 174
11.4 Surveillance 177
11.5 Treatment 178
11.6 Laboratory findings 179
11.7 Function of the gene 181
11.8 The significance of chromosomal region 9q22 181
References 182
12 Xeroderma pigmentosum, Cockayne syndrome and trichothiodystrophy:
sun sensitivity, DNA repair defects and skin cancer 185
Colin F. Arlett and Alan R. Lehmann
12.1 Introduction 185
12.2 Clinical observations 185
12.3 Cellular and biochemical repair studies 187
12.4 XP genes and their products 193
12.5 Relationship to clinical symptoms 199
References 200
Part Four The Common Cancers 207
13 Genetics and the common cancers 208
Richard S. Roulston and Julian Peto
13.1 Introduction 208
13.2 Inherited cancer syndromes 208
13.3 Familial clustering of common cancers 209
13.4 Genes of low penetrance predisposing to cancer 218
13.5 Conclusions 220
References 221
14 Familial breast cancer 227
David E. Goldgar, Michael R. Stratton and Rosalind A. Eeles
14.1 Introduction 227
14.2 Familial risk of breast cancer 227
14.3 Familial associations of breast and other cancers 231
14.4 Implications of major genes in breast cancer aetiology 232
14.5 Gene mapping studies in familial breast cancer 233
14.6 Other genes conferring increased risk of breast cancer 233
14.7 The search for additional breast cancer susceptibility genes 234
viii
Contents
14.8 Summary 236
References 236
15 The breast-ovarian cancer syndrome and BRCA1 239
Deborah Ford and Douglas F. Easton
15.1 Introduction 239
15.2 Linkage to chromosome 17 q 239
15.3 The cloning of BRCAI 240
15.4 Genetic heterogeneity 242
15.5 Risks of cancer in BRCAI mutation carriers 243
15.6 Estimates of the gene frequency of BRCAI 248
15.7 The contribution of BRCAI to breast and ovarian cancer incidence 249
15.8 Conclusions 250
References 251
16 Screening for breast cancer in high-risk populations 253
Jocelyn Chamberlain
16.1 Introduction 253
16.2 The effect of screening on breast cancer mortality 254
16.3 Disadvantages of screening average-risk women 257
16.4 Balance of benefits and disadvantages 261
16.5 Implications for women at inherited risk of breast cancer 261
16.6 Guidelines for current practice 263
16.7 Conclusion 264
References 264
17 The management of women with a high risk of breast cancer 267
I The role of prophylactic tamoxifen
Trevor J. Powles and Mary E.R. O'Brien
17.1 Introduction 267
17.2 Experimental and clinical basis for tarnoxifen use 268
17.3 Duration of treatment and dosage 268
17.4 Tamoxifen prevention trials 269
17.5 Potential adverse effects of tamoxifen 270
17.6 Future developments of tamoxifen as a chemopreventive agent 271
17.7 Conclusions 271
References 271
II The controversy of prophylactic mastectomy 273
Timothy I. Davidson and Nigel P.M. Sacks
17.8 Introduction 273
17.9 Indications for prophylactic mastectomy 274
17.10 Surgical technique 276
17.11 Psychosocial and psychosexual sequelae 279
17.12 Conclusions 280
References 280
ix
Contents
18 Psychological distress associated with genetic breast cancer risk 282
Kathryn M. Kash
18.1 Introduction 282
18.2 Genetic risk 283
18.3 Psychological issues 283
18.4 High-risk clinic - experience from the Strang Cancer Prevention Center 284
18.5 Conclusions 287
References 288
19 Familial ovarian cancer 290
Bruce AJ. Ponder
19.1 Genetic epidemiology 290
19.2 Molecular genetics 291
19.3 Clinical implications: the management of ovarian cancer families 293
References 296
20 Familial colon cancer syndromes and their clinical management 297
Victoria A Murday, D. Timothy Bishop and Nigel R. Hall
20.1 Introduction 297
20.2 Syndromes associated with an increased risk of colorectal cancer 298
20.3 Diagnosis and management 302
20.4 Discussion 303
References 304
21 The genetics of familial colon cancer 306
Susan M. Farrington and Malcolm G. Dunlop
21.1 Introduction 306
21.2 Familial adenomatous polyposis (FAP) 307
21.3 Hereditary non-polyposis colorectal cancer (HNPCC) 309
21.4 Practical implications for the discovery of colorectal cancer
susceptibility genes 316
References 316
22 Familial prostate cancer and its management 320
Rosalind A Eeles and Lisa Cannon-Albright
22.1 Introduction 320
22.2 Evidence for a genetic predisposition to prostate cancer 320
22.3 Studies of familial prostate cancer in the Utah population 321
22.4 Epidemiological evidence that the increased risk to relatives
is a genetic effect 324
22.5 The genetic model 325
22.6 Coaggregation of prostate cancer with other cancers 325
22.7 The search for gene(s) predisposing to familial prostate cancer 326
22.8 Clinical considerations 328
22.9 Summary 329
References 330
x