Polygenic risk of any, metastatic, and fatal prostate cancer in the Million Veteran Program.

BACKGROUND: Genetic scores may provide an objective measure of prostate cancer risk and thus inform screening decisions. We evaluated whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with prostate cancer risk in a diverse population, including Black men, who have higher average risk of prostate cancer death but are often treated as a homogeneously high-risk group. METHODS: This was a retrospective analysis of the Million Veteran Program, a national, population-based cohort study of US military veterans conducted 2011-2021. Cox proportional hazards analyses tested for association of genetic and other risk factors (including self-reported race and ethnicity and family history) with age at death from prostate cancer, age at diagnosis of metastatic (nodal or distant) prostate cancer, and age at diagnosis of any prostate cancer. RESULTS: A total of 590 750 male participants were included. Median age at last follow-up was 69 years. PHS290 was associated with fatal prostate cancer in the full cohort and for each racial and ethnic group (P < .001). Comparing men in the highest 20% of PHS290 with those in the lowest 20% (based on percentiles from an independent training cohort), the hazard ratio for fatal prostate cancer was 4.42 (95% confidence interval = 3.91 to 5.02). When accounting for guideline-recommended risk factors (family history, race, and ethnicity), PHS290 remained a strong independent predictor of any, metastatic, and fatal prostate cancer. CONCLUSIONS: PHS290 stratified US veterans of diverse ancestry for lifetime risk of prostate cancer, including metastatic and fatal cancer. Predicting genetic risk of lethal prostate cancer with PHS290 might inform individualized decisions about prostate cancer screening.