Genetic etiology of sporadic ovarian cancer

Introduction Ovarian cancer presents as familial clusters and as sporadic cases without strong family history. As summarized elsewhere in this book, rare mutations conferring substantially increased ovarian cancer risk (up to 50%) occur in several genes including BRCA1 and BRCA2 [9,10], mismatch repair genes such as MLH1 and MSH2 [11], and other DNA repair genes, such as RAD51C [12]. Yet, these high-risk variants are very rare (less than 1% in most populations), and they are estimated to account for less than 40% of the excess familial risk of ovarian cancer [13]. Here, we describe the genetic etiology of sporadic ovarian cancer (i.e., ovarian cancers that do not arise from within high-risk familial clusters). We review evidence that ovarian cancer is genetic, data on particular genes which have been studied as candidates, results from searches throughout the genome for ovarian cancer risk factors, strategies for follow-up of genomic regions harboring risk loci, and approaches for the identification and characterization of additional genetic factors. Evidence for low-penetrance loci The role of inherited factors in ovarian cancer susceptibility is suggested by numerous epidemiologic studies reporting increased risks from 2- to 10-fold for women with family history of ovarian cancer [14]. In fact, compared with confirmed demographic, reproductive, and lifestyle factors, positive family history is the strongest risk factor for ovarian cancer. Increased familial risk can be explained, in part, by shared environmental factors; however, studies of twins and migrants provide additional support for genetic heritability of the disease. For example, identical twins are more likely to have the same ovarian cancer disease state than fraternal twins [15]. In addition, genetic epidemiologic models suggest that a large number of additional rare high-risk variants, such as BRCA1 or BRCA2 is unlikely to exist [16].