PROJECT SUMMARY The natural history of high-risk, localized prostate cancer, accounting for a substantial proportion of the 29,000 prostate cancer–related deaths per year in the U.S., is highly variable: there are patients who are cured with surgery or radiation, while others develop metastases and succumb to their disease. To date, attempts to stratify patients within these subsets of high-risk, localized prostate cancer have proven inadequate. There is particular urgency within the African American population, where risk of lethal disease is highest. There is a tremendous need for biomarkers that can reliably distinguish the most aggressive forms of disease within high- risk groups. Specifically, we focus on the DNA damage repair (DDR) pathway, where certain variants appear to be associated with prostate cancer aggressiveness. In this proposal, we will address two important questions in the field: 1) Among patients with high-risk, localized prostate cancer, can we identify genetic aberrations in DDR pathway associated with the most aggressive forms of the disease? 2) Do DDR variants contribute to increased risk of aggressive prostate cancer among African American men? In the first aim, we focus on inherited germline variants in the DDR pathway. Using large retrospective and prospective cohorts of patients with high-risk, localized prostate cancer, we will perform sequencing in DNA derived from blood samples and examine associations with development of lethal prostate cancer over long- term follow-up. In our second aim, we will interrogate the somatic genome and matched germline using DNA derived from radical prostatectomy specimens and corresponding blood samples, and we will study associations with lethal disease. In the third aim, we will determine the prevalence of germline DDR in a larger cohort of African American prostate cancer patients and estimate the extent to which DDR mutations contribute to prostate cancer disparities. Completion of the experiments outlined in this proposal will provide an unparalleled look at the association between DDR and lethal forms of prostate cancer. We have the potential to i) discover specific germline and somatic biomarkers for lethal disease that could be used to determine treatment strategies at the time of diagnosis, perhaps using strategies such as PARP inhibition or platinum chemotherapy that target the DDR pathway; ii) discover germline biomarkers that could be developed as screening tools for the most aggressive forms of prostate cancer; and iii) define the extent to which mutations in in DDR pathway genes may explain racial disparities in prostate cancer. The genetic loci and target genes comprising this dataset together with the other projects will stimulate new targets for therapeutic intervention.