GENETIC EPIDEMIOLOGY OF CANCER: FROM FAMILIES TO HERITABLE GENES Kari HEMMINKI 1,2 * , Rajesh RAWAL 1 , Bowang CHEN 1 and Justo Lorenzo BERMEJO 1 1 Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany 2 Department of Biosciences at Novum, Karolinska Institute, Huddinge, Sweden A reliable determination of familial risks for cancer is im- portant for clinical counseling, prevention and understanding cancer etiology. Family-based gene identification efforts may be targeted if the risks are well characterized and the mode of inheritance is identified. Medically verified data on familial risks have not been available for all types of cancer but they have become available through the use of the nationwide Swedish Family-Cancer Database, which includes all Swedes born in 1932 and later with their parents, totaling over 10 million individuals. Over 150 publications have emanated from this source. The familial risks of cancer have been characterized for all main cancers and the contribution of environmental and heritable effects to the familial aggrega- tion has been assessed. Furthermore, the mode of inheri- tance has been deduced by comparing risks from parental and sibling probands. Examples are shown on familial clus- tering of cancers, for which heritable susceptibility genes are yet unknown, such as squamous cell carcinoma of the skin, intestinal carcinoids, thyroid papillary tumors, brain astrocy- tomas and pituitary adenomas. Some common cancers, such as lung and kidney cancers, appear to show an early-onset recessive component because familial risks among siblings are much higher than those in families where parents are probands. Many of the cancer sites showing high familial risks lack guidelines for clinical counseling or action level. In con- clusion, we recommend that any future gene identification efforts, either using linkage or association designs, devise their strategies based on data from family studies. Clinical genetic counseling would benefit from reviewing established familial risks on all main types of cancer. © 2004 Wiley-Liss, Inc. Key words: familial cancer; familial risk; heritability; cancer genes Genetic epidemiology is a discipline elucidating and character- izing the contribution of genetic factors in disease causation, starting from familial clustering of a disease and ending in iden- tification of the underlying genetic mechanisms. Genetic epidemi- ology contributes to the assessment of cancer risks between family members, providing the scientific basis for clinical counseling and helping therapeutic decisions and cancer prevention. Modeling of cancer in families is informative of the modes of inheritance and etiologic apportioning to hereditary and environmental causes. Genetic epidemiologic data are crucial for gene identification strategies and characterization of genotype-specific risks. A further advocacy for the search of heritable cancer genes is that they may also be important in common sporadic cancers: a promise fulfilled for some but not all heritable cancer susceptibility genes known to date. 1 Genetic epidemiology is a relatively new and interdisciplinary science, which has originally dealt with modeling, design and statistical issues in human genetics. At times the integration of genetics and epidemiology was viewed suspiciously by scientists in both disciplines, as described in the introduction to the book Fundamentals of Genetic Epidemiology. 2 In the cancer area, dif- ferent views have culminated on the question of heritable and environmental causes of cancer, in which epidemiologists vigor- ously argued for the latter. On the other hand, the literature on heritable cancers is full of overstatements regarding their preva- lence. Until the end of 1990s, genetic epidemiology has been a small science, but since then it has greatly benefited from the interest in human genome and genetic diseases. With the emer- gence of single nucleotide polymorphisms (SNPs) as versatile tools, studies on gene-environment interactions have become pop- ular, however, with many embedded controversial issues. Mass publication is going on and results are reported without consider- ation of the functionality of SNPs or tissue of expression of the relevant genes in subgroups lacking any biologic rationale. 3 It is ironic that the historical roles of epidemiologists and geneticists appear to be completely changed: the proponents of gene-environ- ment interactions appear to trust the overwhelming importance of heritable factors when they act in concert with environmental factors while geneticists are raising concerns. 4,5 There is a com- mon failure to recognize that SNPs are inherited and that the related studies focus essentially on heritable effects. Thus, any cancer with a small familial effect cannot show large effects in genetic association studies on common polymorphisms. Analo- gously, nesting of an association study in familial cancers is beneficial for statistical power. 6–8 We hope that those who plan association studies would take notice of the familial risks and proportions presented in this review. In this review, we discuss familial risks in the main types of cancer, based on results from the Swedish Family-Cancer Data- base, which is the largest data set of familial cancer ever used. For unbiased risk estimates, it is important that all data on cancers are medically verified and that family structures are derived from registered sources. This review will not be a synopsis of the 150 publications from the Database. Rather, we will focus on examples on clinical implications of the results and on their guidance to gene identification efforts. We will point out cancers and population subgroups that would appear particularly amenable to molecular analysis. We use the term “familial” to denote cancers in 2 or more first-degree relatives and heritable when an inherited gene defect is known or inferred due to a high risk. 9 CONCEPTS AND DATA SOURCES Familial risk of a disease is a measure of its clustering in family members. Commonly, familial risk is defined between those who have a relative (e.g., parent or sibling) with cancer compared to those whose relatives are free from cancer. The risk can be given as a relative risk or standardized incidence ratio (SIR). The SIRs presented here have been adjusted for age, socioeconomic status and many other variables specified in the original studies. In general, with the exception of age, none of the variables available in the Family-Cancer Database appear to confound familial risk. Grant sponsor: Deutsche Krebshilfe; Grant sponsor: the Swedish Cancer Society. *Correspondence to: Division of Molecular Genetic Epidemiology, Ger- man Cancer Research Center, Im Neuenheimer Feld 580, D-69120 Hei- delberg, Germany. Fax: +49-6221-421-810. E-mail: k.hemminki@dkfz.de Received 1 September 2003; Accepted after revision 26 March 2004 DOI 10.1002/ijc.20355 Published online 20 May 2004 in Wiley InterScience (www.interscience. wiley.com). Int. J. Cancer: 111, 944 –950 (2004) © 2004 Wiley-Liss, Inc. Publication of the International Union Against Cancer