Germline sequencing for genetic markers of aggressive prostate carcinoma susceptibility. D. Koboldt1, K. Kanchi1, D. Larson1, R. Fulton1, E. Mardis1, A. Kibel2 1) The Genome Institute, Washington University, 4444 Forest Park Pkwy., Saint Louis, MO; 2) Dana Farber Cancer Center, 45 Francis Street, Boston, MA.

   Prostate cancer (PCa) is the second most common cancer among men in the United States and a growing medical problem worldwide. Most men will develop histologic prostate cancer, but few will be diagnosed with aggressive disease. Unfortunately, the most common screening tool (PSA) is not effective for making this prognosis. Several groups have sought genetic markers for risk of aggressive PCa. While GWAS approaches have identified and validated several PCa risk loci, none of the variants have been reproducibly linked to aggressive disease. One possible explanation for this is that genetic predisposition for aggressive PCa is driven by rare, functionally disruptive variants not interrogated by SNP arrays. To search for such variants, we performed exome sequencing in two populations: European-Americans (150 cases, 150 controls) and African Americans (122 cases, 150 controls). The latter are an important population to study for PCa; African-American men have a higher risk of disease, more advanced tumors at presentation, and a worse prognosis compared to European-Americans. Exome sequencing uncovered ~30,000 and ~35,000 rare, potentially-deleterious variants in the European-American and African-American cohorts, respectively. Gene-based burden tests revealed ~400 genes with significant case-control differences. Targeted sequencing of these genes in an independent cohort of 835 samples (223 cases, 612 controls) confirmed associations for 35 genes. In European-Americans, associated genes included PCSK6, encoding a proprotein convertase thought to play a role in tumor progression; and DMBT1, a candidate tumor suppressor gene for brain, lung, esophageal, gastric, and colorectal cancers. In African-Americans, among the associated genes were DCLRE1A, a regulator of mitotic cell checkpoint; and TRPM2, encoding a Ca(2+)-permeable channel that is activated by oxidative stress and confers susceptibility to cell death. Importantly, few genes showed evidence of association in both European-Americans and African-Americans, suggesting that population genetic differences may underlie the contrast in disease susceptibility between these groups.

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