Despite being the most common cancer diagnosed in men in the U.S., an understanding of the molecular mechanisms underlying susceptibility for prostate cancer remains elusive. Segregation analyses suggest the existence of dominant high risk prostate cancer susceptibility alleles, which may account for up to 10 percent of all prostate cancer cases. Although linkage analysis of hereditary prostate cancer (HPC) is complicated by a number of barriers, research groups in the U.S. and Europe have implicated at least six loci as harboring HPC genes. These initial studies emphasize the extensive heterogeneity that characterizes HPC. To address and overcome the difficulties that this heterogeneity presents for HPC gene mapping and identification, the International Consortium for Prostate Cancer Genetics was established. The 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 1700 prostate cancer families, each having at least three first degree relatives affected with prostate cancer, making this combined resource unique and by far the largest one of its kind. The size and diversity of this consortium make it ideally suited to address questions in molecular genetics of prostate cancer, including those involving genetic heterogeneity, other cancers segregating in prostate cancer families, and gene frequency and penetrance of HPC once they are cloned. In this proposal, funds are requested to support the development and use of the combined resources of the ICPCG to perform systematic analyses to identify and characterize prostate cancer susceptibility loci. Specifically, we propose to : 1) analyze the complete family collection for evidence of linkage at both previously identified loci (e.g. 1p36, 1q43-43, 17p11, 20q13, Xq27-28) and novel loci identified over the course of the funding period; 2) carry out combined linkage analyses following stratification of families based upon clinical and family parameters to examine linkage in defined subsets of families; 3) develop new methodologies to optimize and facilitate the analysis of this unique dataset. It is anticipated that this combined resource and the studies made possible by its development will provide an unprecedented opportunity to characterize and unravel the complexities of genetic susceptibility for this common disease.
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