Prostate cancer is the most commonly diagnosed male malignancy in the US with an estimated 33% of all new male cancer diagnoses and 9% of all cancer deaths in 2006. Progress in finding reproducible prostate cancer risk variants has been slow even though family and twin studies show that there is a significant genetic component to the disease. Using a combination of linkage and association analysis, we identified a common genetic variant on chromosome 8q24 that is significantly associated with an increased risk of prostate cancer. Importantly, we have replicated our findings in two populations of European origin and one African American. The variant explains about 8% of prostate cancer risk in populations of European ancestry but up to 16% of the risk in African Americans and may partly explain the higher incidence of prostate cancer in this group. Our findings have now been replicated in Japanese American, Native Hawaiian, Latino American and European American prostate cancer case-control series lending additional support to the presence of risk variants in this region that are important in a wide spectrum of populations. The association signal is located within a linkage disequilibrium block on Chr8q24. This genomic region contains no known genes but is frequently gained or amplified in prostate cancer as well as other cancer types. To delineate the functional consequences of carrying the at risk variant(s) we propose to thoroughly analyze a 2 Mb region on Chr8q24 centered on the genomic region containing the markers that associate significantly to prostate cancer. We will use several complementary high-resolution array based technologies to uncover transcripts, copy number variants and methylated sites in the Chr8q24 region and relate these to the prostate cancer risk variant(s). We thus propose to take the first steps towards identifying the underlying functional prostate cancer risk factor on Chr8q24 and begin to explain why carriers are at an increased risk of developing prostate cancer. A better understanding of the prostate cancer risk factor on Chr8q24 is important for several reasons. First, it will increase our knowledge of how possibly minor differences in normal cellular physiology can over time lead to prostate cancer. Second, this information may unveil new cellular mechanisms that affect predisposition to prostate cancer and possibly other cancer types. Last, but not least, increased knowledge about the functional aspects of predisposition to prostate cancer may lead to the development of new methods for diagnosing and treating the disease.