The Genetics of Cancer

221 Pages·1995·4.207 MB·English

by  D. Eccles, R. Houlston (auth.), B. A. J. Ponder, M. J. Waring (eds.)

THE GENETICS OF CANCER
A catalogue record for this book is available from the British Library
Library of Congress Cataloging in Publication Data
The genetics of cancer! edited by B.A.J. Ponder and M.J. Waring.
p. cm. -- (Cancer biology and medicine ; CABM 04)
Includes bibliographical references and index.
ISBN 978-94-010-4294-9 ISBN 978-94-011-0677-1 (eBook)
00110.1007/978-94-011-0677-1
1. Cancer--Genetic aspects. 1. Ponder. B. A. J. (Bruce A. J.).
1944- II. Waring. Mlchael J. III. Series.
[ONLM: 1. Neoplasms--genetics. W1 CA673L v.4 1995 I az 202
G33193 19951
RC268.4.G459 1995
616.99'4042--dc20
ONLM/OLC
for Library of Congress 95-31821
CIP
Copyright
© 1995 by Springer Science+Business Media Dordrecht
OriginaHy published by Kluwer Academic Publishers in 1995
Softcover reprint ofthe hardcover lst edition 1995
AH rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or
transmitted in any form or by any means, electronic, mechanical, photocopying, recording or
otherwise, without prior permission from the publishers, Springer Science+Business Media, B.V.
Typeset by EXPO Holdings, Malaysia
Distributors
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for all other countries: Kluwer Academic Publishers Group, Distribution Center, PO Box 322,
3300 AH Dordrecht, The Netherlands
A catalogue record for this book is available from the British Library
ISBN 0-7923-8886-0
Library of Congress Cataloging in Publication Data
The genetics of cancer! edited by B.A.J. Ponder and M.J. Waring.
p. cm. -- (Cancer biology and medicine; CABM 04)
Includes bibliographical references and index.
ISBN 0-7923-8886-0 (casebound alk. paper)
1. Cancer--Genetic aspects. I. Ponder, B. A. J. (Bruce A. J.),
1944- II. Waring, Michael J. III. Series.
[ONLM: 1. Neoplasms--genetics. W1 CA673L v.4 1995 I az 202
G33193 19951
RC268.4.G459 1995
616.99·4042--dc20
ONLM/OLC
for Library of Congress 95-31821
CIP
Copyright
© 1995 by Kluwer Academic Publishers
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or
transniitted in any form or by any means, electronic, mechanical, photocopying, recording or
otherwise, without prior permission from the publishers, Kluwer Academic Publishers BV,
PO Box 17, 3300 AA Dordrecht, The Netherlands.
Published in the United Kingdom by Kluwer ~cademic Publishers, PO Box 55, Lancaster, UK.
Kluwer Academic Publishers BV incorporates the publishing programmes ofD. Reidel, Martinus
Nijhoff, Dr W. Junk and MTP Press.
Typeset by EXPO Holdings, Malaysia
Printed and bound in Great Britain by Hartnolls Ltd., Bodmin, Cornwall.
Contents
List of Contributors vii
Preface ix
1. Breast cancer genetics
D. Eccles and R. Houlston 1
2 The genetics of lung cancer
N.E. Caporaso 21
3 Colorectal cancer
J.D. Potter, T.A. Sellers and S.S. Rich 45
4 The genetics of prostate cancer
R.A. Eeles 67
5 Lessons from developmental biology
E. T. Stuart and P. Gruss 85
6 Animal models for the study of genetic susceptibility to cancer
M.N. Gould 99
7 Animal models to look for polygenic effects in cancer predisposition
T.A. Dragani and M.A. Pierotti 111
8 Human repair deficiencies and predisposition to cancer
M. Hall, P.G. Norris and R.T. Johnson 123
9 Implications of studies of inherited predisposition for prevention
and treatment
CM. Steel 159
10 Mutagenic properties of anticancer drugs
L.R. Ferguson 177
Index 217
v
List of Contributors
N.E. CAPORASO Private Bag 92019
Genetic Epidemiology Branch Auckland
National Cancer Institute New Zealand
National Institutes of Health
EPN 439 M.GOULD
Rockville Department of Human Oncology
MD20892 University of Wisconsin-Madison
USA K4/332 Clinical Science Center
600 Highland Avenue
T.A. DRAGANI Madison
Division of Experimental WI 53792
Oncology A USA
Istituto Nazionale Tumori
Via G. Venezian 1 P.GRUSS
1-20133 Milan Department of Molecular Cell
Italy Biology
Max Planck Institute for Biophysical
D.ECCLES Chemistry
Wessex Clinical Genetics Service Am Fassberg
Level G D-37018 Gottingen
Princess Anne Hospital Germany
Southampton
S0165YA M.HALL
UK Cancer Research Campaign
Mammalian Cell DNA Repair Group
R.A.EELES Department of Zoology
Institute of Cancer Research and University of Cambridge
Royal Marsden Hospital . Cambridge
Downs Road CB23EJ
Sutton UK
Surrey
SM25PT R.HOULSTON
UK Section of Epidemiology
Institute of Cancer 2
L.R. FERGUSON Research
Cancer Research Laboratory Sutton
University of Auckland Medical Surrey SM2 5NG
School UK
vii
LIST OF CONTRIBUTORS
R.T. JOHNSON S.S. RICH
Cancer Research Campaign Bowman Gray School of Medicine
Mammalian Cell DNA Repair Group Wake Forest University
Department of Zoology Medical Center Blvd.
University of Cambridge Winston-Salem, NC 27157-1063
Cambridge USA
CB23EJ
UK T.A. SELLERS
Division of Epidemiology
University of Minnesota
P.G.NORRIS
School of Public Health, Suite 300
Department of Dermatology
1300 South Second Street
Addenbrooke's NHS Trust
Minneapolis
Hills Road
MN 55454-1015
Cambridge
USA
CB22QQ
UK
C.M.STEEL
M.A. PIEROTTI School of Biological and Medical
Division of Experimental Sciences
Oncology A University of St. Andrews
Istituto Nazionale Tumori Bute Medical Building
Via G. Venezian 1 St. Andrews
1-20133 Milan Fife KY16 9TS
Italy UK
J.D. POTTER E.T.STUART
Cancer Prevention Research Program Department of Molecular Cell Biology
Fred Hutchinson Cancer Research Max Planck Institute for Biophysical
Center Chemistry
1124 Columbia, MP 702 Am Fassberg
Seattle, W A 98104 D-37018 G6ttingen
USA Germany
viii
Preface
Families in which there seems to be inheritance of cancer have been recognized
for almost 200 years. Only in the past decade, however, have molecular genetics
and epidemiology combined to define the role of inheritance in cancer more
clearly and to identify some of the genes involved.
Using cancer-prone families, the causative genes can be tracked down by
genetic linkage and positional cloning. Several of these genes have subsequently
proved to play critical roles in normal growth and development. There are also
implications for the families themselves as regards genetic testing, with its atten
dant dilemmas if it is not clear that useful action will result.
The chapters in this volume illustrate what has already been achieved, but
also look critically at the future directions of this research and its potential clini
cal application.
IX
1
Breast cancer genetics
D. Eccles and R. Houlston
INTRODUCTION
The observation that some families have an excess of breast cancers, not readily
accounted for by chance, is not new. Breast cancer families have been recog
nized since Ancient Roman times 1• One of the earliest and most striking pub
lished reports was by a French physician, Paul Broca, who in 1866 reported a
four-generation family where breast cancer had affected ten out of twenty-four
women2. It is only in the last 10 years, however, that significant advances have
led to a better understanding of familial clustering of this disease.
Systematic epidemiological studies of familial risks have shown an
increased risk of breast cancer in the relatives of breast cancer patients.
Results from segregation analyses of pedigrees have suggested that, whilst the
majority of breast cancer cases are sporadic, around 5-10% of cases can be
attributed to a highly penetrant gene which is dominantly inherited. Molecular
genetic studies have directly implicated some specific loci predisposing to
breast cancer.
The aim of this chapter is to review the evidence supporting a role for genetic
factors in breast cancer aetiology and to discuss the value of such infonnation in
clinical practice.
GENETIC EPIDEMIOLOGY OF BREAST CANCER
Case-control and cohort studies of familial breast cancer risks
Case-control and cohort studies of the familial risks of breast cancer have been
published by a number of workers3-9• All have demonstrated a significant
familial risk of around two-fold. Of the published studies, the largest by far is
that based on the Cancer and Steroid Honnone (CASH) Study conducted by the
Centres for Disease ControllO• This study is based on the family histories of
4730 confinned cases of breast cancer, diagnosed between the ages of 20 and
54, and 4688 matched controls. Since this is to date the largest and most
detailed population-based study of familial breast cancer, it will be referred to
extensively.
1
THE GENETICS OF CANCER
A number of features of the familial breast cancer risk suggest that a propor
tion of breast cancers can be attributed to the inheritance of a highly penetrant
gene, with the proportion of genetic cases being greatest at younger ages.
Firstly, familial breast cancer risk is strongly age dependent. For example, in the
CASH study, the risk in relatives was 5-fold greater if the case was diagnosed
before the patient was 40 years old compared with less than 2-fold if diagnosed
after age 50. Secondly, the risk of breast cancer is greater in women with two or
more affected first-degree relatives than in women with only one affected rela
tive, and thirdly, familial risks are greater in relatives of bilateral metachronous
cases than in relatives of unilateral cases.
Segregation studies of breast cancer
Possible genetic models of familial breast cancer have been formally tested
using segregation analysis by a number of workers 10-13. All have found
support for the inheritance of a dominant gene underlying the familial aggrega
tion of breast cancer. Those studies based upon high-risk families, i.e. those
selected for multiply affected relatives, are fundamentally less satisfactory than
those based upon unselected series of patients. This is because of the problem of
ascertainment correction and because the genetic basis of breast cancer in
selected families may not necessarily reflect the familial aggregation of breast
cancer observed in the general population.
In the analysis of the CASH dataset, the best fitting model for the familial
aggregation of breast cancer was an autosomal dominant gene with a population
frequency of 0.0033, such that the cumulative risk of breast cancer is 38% by
age 50 and 67% by age 70 in gene carriers, compared with 1.5% and 5%
respectively in non-carriers. Under this dominant model, the proportion of breast
cancer cases attributable to the deleterious gene falls from approximately 35%
among cases of breast cancer diagnosed below age 30 to 1% in cases diagnosed
after age 80.
A number of epidemiological studies have demonstrated a higher risk of
breast cancer in sisters of affected cases than in mothers. If real, this is a feature
of familial breast cancer unaccounted for by a dominant model and could reflect
either the presence of recessive genes predisposing to breast cancer or the effect
of common sibling environment. Alternatively, it could be a reflection of the
Table 1.1 Genetic risks in breast cancer'
Risk category Risk relative to population
First-degree relative of patient over 55 years at diagnosis x 1.6
First-degree relative of patient under 55 years at diagnosis x2.3
First-degree relative of patient under 45 years at diagnosis x3.8
First-degree relative of patient with bilateral breast cancer x 6.4
• Based on Houlston et al., 199218
2
BREAST CANCER GENETICS
temporal trend of increasing breast cancer incidence which has also been
observed in familial breast cancerl4.
Relationship of familial breast cancer to other cancers
A striking feature of familial breast cancer is the association of familial breast
cancer with other cancers. There are many anecdotal reports of families with
multiple cases of early-onset breast cancer and ovarian cancer which are consis
tent with the inheritance of a dominant gene with pleiotropic effects 15. This
association is supported by epidemiological studies of breast and ovarian cancer
which have found that the risk of ovarian cancer increased by 1.3-1.7-fold in
relatives of breast cancer patients and vice versal6.
The other cancer type for which a familial association with breast cancer is
well established is childhood bone and soft-tissue sarcomas. This association
undoubtedly reflects in part the contribution of the Li-Fraumeni syndrome to the
overall total burden of breast cancer risk.
The evidence for an association between breast and other cancers is more
tenuous. There is some evidence from both case reports of high-risk families
and epidemiological studies for an association between breast and prostatic
cancer9,17,18. The risk of prostatic cancer in relatives of breast cancer patients
has been variously reported as increased between 2.2- and 3-fold. However,
Peto and co-workers (unpublished data), in a large cohort study, found a rela
tive risk of only 1.1, giving less support for such an association. Taken
together, all studies would be compatible with an increased risk of around 1.3-
fold. An association has also been reported between breast and uterine cancer
by Anderson et al. 8, and Tulinius et al. 9. Schildkraut et al. 16, however, found a
significant correlation between cancers of the ovary and breast, but no
significant association was observed between endometrial and either ovarian
or breast cancer. Other associations have been reported between breast cancer
and cancers of the lung8 and thyroidl9,20. It is noteworthy that an association
bet\1'een thyroid cancer and breast cancer exists as a feature of Cowden
syndrome.
BREAST CANCER GENES
There are a number of rare genetic conditions with distinct phenotypes which
are associated with an increase in the risk for breast cancer (e.g. Cowden disease
and Peutz-Jeghes syndrome). These conditions are clinically and genetically
distinct from the hereditary breast and breast/ovarian cancer families, in which
there is no consistently recognizable phenotype which will distinguish gene car
riers from non-carriers in a family before the onset of malignant disease. The
high incidence of sporadic breast cancer in the population and the lack of a rec
ognizable carrier phenotype complicates linkage studies. The emergence of the
polymerase chain reaction as a simple but powerful laboratory tool has consider
ably increased the amount of family material for linkage studies because pathol
ogy material from deceased family members can now be utilized. There are at
3