Genetic Risk Prediction for Prostate Cancer: Implications for Early Detection and Prevention

Context: Prostate cancer (PCa) is a leading cause of death and partially heritable. Genetic risk prediction might be useful for strategies to reduce PCa mortality through early detection and prevention.Objective: To review evidence for genetic risk prediction for PCa. Evidence acquisition: A collaborative literature review was conducted using PubMed and Google Scholar. Search terms included genetic, risk, prediction, and "prostate cancer". Articles addressing screening, early detection, or prevention were prioritized, as were studies involving diverse populations.Evidence synthesis: Rare pathogenic mutations (RPMs), especially in DNA damage repair genes, increase PCa risk. RPMs in BRCA2 are most clearly deleterious, conferring 2-8.6 times higher risk of PCa and a higher risk of aggressive disease. Common genetic variants can be combined into genetic risk scores (GRSs). A high GRS (top 20-25% of the popula-tion) confers two to three times higher risk of PCa than average; a very high GRS (top 1- 5%) confers six to eight times higher risk. GRSs are not specific for aggressive PCa, pos-sibly due to methodological limitations and/or a field effect of an elevated risk for both low-and high-grade PCa. It is challenging to disentangle genetics from structural racism and social determinants of health to understand PCa racial disparities. GRSs are indepen-dently associated with a lethal PCa risk after accounting for family history and race/ ancestry. Healthy lifestyle might partially mitigate the risk of lethal PCa.Conclusions: Genetic risk assessment is becoming more common; implementation stud-ies are needed to understand the implications and to avoid exacerbating healthcare dis-parities. Men with a high genetic risk of PCa can reasonably be encouraged to adhere to a healthy lifestyle.Patient summary: Prostate cancer risk is inherited through rare mutations and through the combination of hundreds of common genetic markers. Some men with a high genetic