Project 1: Molecular Predictors of Prostate Cancer Progression and Mortality

PROJECT SUMMARY Prostate cancer (PC) remains a leading cause of cancer-related morbidity and mortality and represents one of the largest health disparities in the US, with men of African ancestry having the highest incidence and mortality rates. Additional risk factors for PC include older age, family history of PC, and germline genetics. We previously reported that rare germline variants in DNA repair genes (gDRG) are enriched in men with lethal/metastatic PC. We have also developed a novel multi-ancestry polygenic risk score (PRSm) that is highly predictive of PC risk across diverse populations and associated with a younger age at PC diagnosis and conversion from active surveillance to treatment. The combined impact of gDRG and PRS on PC progression is not well understood, particularly in multi-ancestry patients. In this Project, we will use a population-based approach to identify and recruit diverse, non-European, multi-ancestry PC patients, examine the interplay between rare variants in gDRG (e.g., BRCA2) with PRSm and the association with PC clinical features. To accomplish this, we will also develop a clinical-grade paired tumor-germline assay, which will additionally enable large-scale examination of gDRG in combination with high PRSm using tumor molecular profiles. We will also parse out specific, individual variants that contribute the greatest effect on a high PRSm, Finally, we will conduct a tailored PC screening clinical trial for individuals at highest risk of PC due to gDRG and determine patterns of interest, enrollment and adherence to PC screening. Together, we seek to address and mitigate health care disparities related to prostate cancer genetics, and the factors influencing clinical implementation. Ultimately, we seek a better understanding of the interplay between rare gDRG variants and PRSm for a combined analysis of germline genetic information to improve risk prediction and tailored PC screening for men across a broader populations.