Vol 10 733 741 July 2001 Cancer Epidemiology Biomarkers Prevention Review The Genetic Epidemiology of Cancer Interpreting Family and Twin Studies and Their Implications for Molecular Genetic Approaches Neil Risch1 Department of Genetics Stanford University School of Medicine Stanford California 94305 5120 and Division of Research Kaiser Permanente Oakland California 94611 5714 Abstract The recent completion of a rough draft of the human genome sequence has ushered in a new era of molecular genetics research into the inherited basis of a number of complex diseases such as cancer At the same time recent twin studies have suggested a limited role of genetic susceptibility to many neoplasms A reappraisal of family and twin studies for many cancer sites suggests the following general conclusions a all cancers are familial to approximately the same degree with only a few exceptions both high and low b early age of diagnosis is generally associated with increased familiality c familiality does not decrease with decreasing prevalence of the tumor in fact the trend is toward increasing familiality with decreasing prevalence d a multifactorial polygenic threshold model fits the twin data for most cancers less well than single gene or genetic heterogeneity type models e recessive inheritance is less likely generally than dominant or additive models f heritability decreases for rarer tumors only in the context of the polygenic model but not in the context of singlelocus or heterogeneity models g although the family and twin data do not account for gene environment interactions or confounding they are still consistent with genes contributing high attributable risks for most cancer sites These results support continued search for genetic and environmental factors in cancer susceptibility for all tumor types Suggestions are given for optimal study designs depending on the underlying architecture of genetic predisposition Introduction Last June human genome scientists announced completion of and more recently published a rough draft of the human genome sequence ushering in a new era of human molecular genetics 1 2 This accomplishment was heralded with great fanfare and with predictions of a significant impact on the understanding and treatment of chronic human diseases such as cancer It is perhaps for this reason that a recent twin study of cancer 3 received so much attention from both the scientific and lay media because its conclusion was that susceptibility to cancer is primarily environmental and not inherited and thus seem Received 2 1 00 revised 4 27 01 accepted 5 2 01 1 To whom requests for reprints should be addressed at Department of Genetics M322 Stanford University School of Medicine Stanford CA 94305 5120 Fax 650 725 1534 E mail risch lahmed stanford edu ingly at odds with the claims of the genomicists The fact that this was by far the largest twin study in cancer yet reported nearly 45 000 twin pairs also lent credence to this conclusion although an editorial appearing in the same issue 4 discussed some of the limitations of that study Given the increasing emphasis on molecular genetic approaches to address familial disorders coupled with the latest evidence questioning the role of genetics in cancer susceptibility a reassessment of the role of genetic factors in cancer susceptibility generally and for site specific cancers in particular appears warranted Study Designs Familial aggregation of a trait is a necessary but not sufficient condition to infer the importance of genetic susceptibility because environmental and cultural influences can also aggregate in families leading to family clustering and excess familial risk Family aggregation is usually assessed by studying relatives of affected subjects and contrasting their rates of illness with those of a suitable control group typically the relatives of unaffected subjects Several approaches for disentangling genetic from environmental influences are also possible in studies of human disease although practical difficulties often limit their use The most powerful design examines risks in biological relatives of affected versus control adoptees because adoption creates a separation between an individual s biological and environmental influences Because it is often difficult to obtain access to information on biological relatives of adoptees adoption studies typically focus only on common disease or trait outcomes Another study design often used to separate genetic and environmental influences involves twins Identical MZ2 twins derive from the fission of a single fertilized egg and thus inherit identical genetic material By contrast fraternal DZ twins derive from two distinct fertilized eggs and thus have the same genetic relationship as full siblings although they may be more biologically related because of sharing the same prenatal intrauterine experience Comparing the similarity of MZ twins with same sex DZ twins is a common approach for gleaning the magnitude of genetic influence on a disease or trait and has been applied extensively to a broad range of disorders including cancer A standard measure of similarity used in twin studies is the concordance rate The pairwise concordance is calculated simply as the proportion of twin pairs with both twins affected of all ascertained twin pairs with at least one affected On the other hand the probandwise concordance allows for double counting of doubly ascertained twin pairs and has the advantage of being interpretable as the recurrence risk in a co twin of an affected individual 5 Usually the most critical assumption in 2 The abbreviations used are MZ monozygotic DZ dizygotic MFT multifactorial threshold FRR family risk ratio SIR standardized incidence ratio PAF population attributable fraction RR relative risk 733 734 Review The Genetic Epidemiology of Cancer twin studies is that MZ and DZ twins display a comparable degree of similarity because of the sharing of environmental factors so that the difference in concordance rates between MZ and DZ twins is only a reflection of genetic factors Genetic Models and the Interpretation of Family and Twin Studies Understanding empirical evidence about genetic susceptibility to cancer requires a discussion of models of genetic inheritance and their implications The simplest way to measure genetic effects is through familial risk ratios defined as the risk to a given type of relative of an affected individual divided by the population prevalence
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