Abstract – Project 3 It has long been known that African American men experience a higher incidence and increased mortality from prostate cancer compared to men of other ethnic groups. Socio-economic factors and unequal access to health care undoubtedly contribute to this disparity; however, differences in incidence and outcome remain after considering these factors. This raises the possibility that differences in tumor biology and/or genetic alterations also contribute to the adverse outcomes linked to African American prostate cancer. The over-arching goal of this Project is to comprehensively interrogate the mutational landscape and oncogenic gene expression patterns present in primary African American prostate cancer. Towards this end, we will characterize ~3,000 tumor samples from the RESPOND cohort using whole-exome sequencing and targeted sequencing. Approximately 1,000 of these tumors will also undergo transcriptome analysis. This data will be used to study the relationship between prostate cancer genetics and tumor aggressiveness, and will be compared to cohorts of men of European descent to determine whether any genetic or transcriptional alterations show differential prevalence as a function of ancestry. In addition, we will use in vitro studies of primary prostate epithelial cells to test whether common prostate cancer alterations exert more robust tumorigenic effects when introduced into non-malignant prostate cells from African American men compared to prostate epithelial cells from white men. This project should enable definitive insights into the somatic genetic alterations characteristic of African American prostate cancer and the role(s) they might play in driving aggressive disease and adverse outcomes within this and potentially other ancestral groups.