Prostate cancer (PC) is the most common non-skin cancer diagnosed in the US, yet little is known about what causes the disease. Twin and segregation studies provide strong evidence for an inherited genetic susceptibility to PC, with an estimated 42% of all cases due to some underlying genetic alteration, and 5-10% due to rare, autosomal dominant mutations. Linkage analyses in families with a pattern of hereditary prostate cancer (HPC) have reported about a dozen loci that may harbor susceptibility genes, but confirmation has been challenging due to disease and locus heterogeneity. One promising approach is to focus on subgroups of HPC families that share a common feature, with the goal of creating a homogeneous subset to enhance power for linkage. Recently several genetic associations between PC and colon cancer (CC) have emerged: 1) genetic variants in known CC genes have been positively associated with PC risk; and 2) a locus at 8q24 has been associated with elevated risks for both PC and CC. Based on these observations, we hypothesize that HPC families with members diagnosed with CC may represent a more homogeneous subgroup for linkage analyses. To investigate this hypothesis, we will utilize data from the Prostate Cancer Genetic Research Study (PROGRESS), which has genotyped 255 HPC families with 421 genome-wide microsatellite markers. Based on baseline and follow-up surveys, we have identified 156 HPC families that include one or more members who have been diagnosed with CC. Using these families, we will perform parametric and non-parametric linkage analyses with the goal of identifying a genetic locus or loci linked to HPC that may also play a role in CC, assuming a pleiotropic genetic effect. Results from this work will be followed-up with fine mapping in promising regions and association studies using existing DNA samples from prior population-based case- control studies of PC. The proposed study may highlight novel regions of the genome that harbor susceptibility genes for HPC and provide important insights into the underlying genetic epidemiology of PC, including hereditary and sporadic forms of this common and complex disease. Project Narrative One in six men in the US will be diagnosed with prostate cancer in their lifetime, leading to 218,890 new cases and 27,050 deaths annually in the US alone. Despite the magnitude of the morbidity and mortality associated with prostate cancer, little is known about what causes this disease or who is at greatest risk. This study aims to identify a genomic region(s) linked to increase susceptibility to prostate cancer. Results from this study will lead to a greater understanding of the genetic epidemiology and underlying molecular biology of prostate cancer, and may ultimately lead to the development of genetic tests to screen for those at highest risk for this common and complex disease. ? ? ?
