Environmental and heritable factors in the causation of cancer. The genetic epidemiology of cancer: Interpreting family and twin studies Week 4, Stat 246, 2002PowerPoint PresentationThe papers in briefSummary of conclusionsSetting the scene, ISetting the scene, IIMore on familial risk ratiosPoints to consider when comparing two types of models for the involvement of genes in disease susceptibilitySingle factor modelsOne-factor models: the joint distribution of parent-offspring genotypesOne-factor models: parent-offspring correlationMultifactorial (polygenic) modelsThreshold models for disease susceptibilityMFT models for disease susceptibilityLichtenstein et al’s analysis of 1211 sets of 22 tablesSummary data and results for stomach cancerComment on relative risksComment on the model fitting and residual degrees of freedomSome comments from the paperA cautionary remarkAdditional referencesRisch’s critique: a beginningProofs of results on previous pagePenetrance functionsNon-genetic cases, more than one gene.Familial relative risks and the MFT modelMZ , DZ and the MFT model with shared environmentRisch’s Table 1 expanded : MZRisch’s Table 1 expanded : DZRisch’s Table 1 expanded : RMDRisch’s Table 1 with shared env : MZRisch’s Table 1 with shared env : DZRisch’s Table 1 with shared env : RMDEvidence of familiality in cancerEvidence from the twin data of Lichtenstein et al (2000)Twin relative risk calculationsRisch’s conclusions from his reanalysis of data from Lichtenstein et al.Heritability versus Attributable Risk.ConclusionsAcknowledgement1Environmental and heritable factors in the causation of cancer. The genetic epidemiology of cancer: Interpreting family and twin studiesWeek 4, Stat 246, 2002Background to and discussion of:Lichtenstein et al, NEJM 343 2000: 78-84, and Risch, Cancer Epi., Biom. & Prev. 10 2001:733-7412 Science, July 27, 2001: Genes Come to the Fore in New Cancer Analysis Last summer, scientists in Sweden and Finland got a lot of publicity when they published a paper, based on data from mammoth Scandinavian twin studies, concluding that inherited factors make a "minor contribution" to most cancers. But they were using the wrong methodology, says genetic epidemiologist Neil Risch of Stanford University. Risch has done an analysis that comes to the opposite conclusion: Genes play a strong role in who gets cancer. Risch looked at the same data as in the earlier study, headed by Paul Lichtenstein of Sweden's Karolinska Institute. In the model Lichtenstein used to extract estimates of the relative contributions of genes and environment to cancer liability, environment nearly always won out. But Risch says that was the wrong model--one problem with it is that there aren't enough people with rare cancers to produce meaningful calculations. Risch instead looked at people in twin and family studies who had developed cancer and then estimated the likelihood that a first-degree family member would develop the same cancer. He found that in "the great majority of cancers," a family member was about twice as likely as the average person to develop the cancer. If anything--contrary to Lichtenstein's conclusions--the genetic risk was higher for rarer cancers, Risch reports in the July issue of Cancer Epidemiology Biomarkers & Prevention. Prostate, colorectal, and breast cancers are usually seen as having the strongest genetic components. But the top three on Risch's list are thyroid and testicular cancers and multiple myeloma. The exercise means that "we should be looking for susceptibility genes for all cancers," says Risch. Lichtenstein was on vacation and unavailable for comment. But cancer epidemiologist Sholom Wacholder of the National Cancer Institute in Bethesda, Maryland, says Risch's work is "a reminder of the need to be cautious about interpreting studies that attempt to distinguish genetic and environmental factors."3The papers in briefLichtenstein et al (2000). Combined data on 44,788 pairs of twins listed in the Swedish, Danish and Finnish twin registries in order to assess the risks of cancer at 28 anatomical sites for the twins of persons with cancer. Statistical modeling was used to estimate the relative importance of heritable and environmental factors in causing cancer at 11 of those sites.Risch (2001). Offers a reassessment of the role of genetic factors in cancer susceptibility generally and for site-specific cancers in particular. Presents an detailed critique of Lichtenstein et al (2000).4Summary of conclusionsLichtenstein et al. “Inherited genetic factors make a minor contribution to susceptibility to most types of cancers. This finding indicates that the environment has the principal role in causing sporadic cancers.”Risch. “ a) All cancers are familial to approximately the same degree, with only a few exceptions; 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 single-locus or heterogeneity models; g) although the family and twin data do not account for gene-environment interaction or confounding, they are still consistent with genes contributing high attributable risks for most cancer sites.”5Setting the scene, I Lichtstenstein et al use the multifactorial (polygenic) threshold (MFT) model, and infer the relative contributions of heredity and environment within that model. Their analysis rests on “the usual assumptions of a classic twin study (that there was random mating, no interactions between genes and environment, and equivalent environments for monozygotic and dizygotic twins). Phenotypic variance was divided into a component due to inherited genetic factors (heritability), a component due to environmental factors common to both members of the pair of twins (the shared
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