Despite being the most common cancer diagnosed in men in the U.S., and a growing burden worldwide, an understanding of the molecular mechanisms underlying susceptibility for prostate cancer (PCa) remains elusive, particularly with respect to inherited risk for clinically relevant, aggressive PCa. Segregation analyses and twin studies are consistent with an important genetic component for PCa risk, providing a strong basis for linkage analyses of PCa families undertaken by research groups in the U.S. and Europe and resulting in implication of many different loci as potentially harboring PCa susceptibility genes. These initial studies emphasize the extensive heterogeneity that characterizes familial PCa. To address and overcome the difficulties that this heterogeneity presents for PCa susceptibility gene mapping and identification, the International Consortium for Prostate Cancer Genetics (ICPCG) was established. This consortium consists of researchers from over 20 institutions in 7 different countries in North America, Europe and Australia, all of whom have extensive, ongoing research programs in this area. Together, this group has collected DNA samples from over 2600 prostate cancer families, including families with 3 or more members affected with aggressive prostate cancer. The size and diversity of this consortium make it ideally suited to address questions in molecular genetics of prostate cancer, including those involving susceptibility gene identification, genetic heterogeneity, other cancers segregating in prostate cancer families, and gene frequency and penetrance of PCa genes once they are identified. In this proposal, we seek the further development and use of the combined resources of the ICPCG to perform systematic analyses to identify and characterize prostate cancer susceptibility genes. Specifically, we propose to: 1) Define the most likely regions harboring prostate cancer susceptibility genes by combining genome wide scan linkage results from -2000 prostate cancer families (including over 110 African American PCa families), with special emphasis on subsets of families with early age at diagnosis, large numbers of affected individuals, and multiple cases with features of clinically aggressive disease; 2) Perform fine mapping in these regions to narrow the region of interest (ROI); 3) Perform dense SNP genotyping to identify and evaluate candidate genes associated with PCa risk in narrowed ROI; 4) Confirm and further characterize any SNPs associated with PCa risk in independent case-control populations; 5) Search for rare variants accounting for linkage in regions where no association is observed. It is anticipated that this combined resource and the studies made possible by its continued analysis will provide an unprecedented opportunity to characterize and unravel the complexities of genetic susceptibility for this common disease. ? ?
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