Evaluating a polygenic hazard score to predict risk of developing metastatic or fatal prostate cancer in the multi-ancestry Million Veteran Program cohort

Importance: Early detection of prostate cancer to reduce mortality remains controversial because there is often also overdiagnosis of low-risk disease and unnecessary treatment. Genetic scores may provide an objective measure of a man9s risk of dying from prostate cancer and thus inform screening decisions, especially in men of African ancestry, who have a higher average risk of prostate cancer death but are often treated as a homogeneous group. Objective: Determine whether a polygenic hazard score based on 290 genetic variants (PHS290) is associated with risk of metastatic or fatal prostate cancer in a racially and ethnically diverse population. Design: Million Veteran Program (MVP) cohort study, 2011-2021. Setting: Nation-wide study of United States military veterans. Participants: Population-based volunteer sample of male participants. Exposure(s): Genotype data were used to calculate the genetic score, PHS290. Family history of prostate cancer and ancestry group (harmonized genetic ancestry and self-reported race/ethnicity: European, African, Hispanic, or Asian) were also studied. Main Outcome(s) and Measure(s): Study designed after MVP data collected. Primary outcome: age at death from prostate cancer. Key secondary outcome: age at diagnosis of prostate cancer metastases. Hypothesis: A germline genetic score (PHS290) is associated with risk of fatal (or metastatic) prostate cancer. Results: 513,997 MVP participants were included. Median age at last follow-up: 69 years. PHS290 was associated with age at death from prostate cancer in the full cohort and for each ancestry group (p<1e-16). Comparing men in the highest 20% of PHS290 to those in the lowest 20%, the hazard ratio for death from prostate cancer was 4.41 [95% CI: 3.9-5.02]. Corresponding hazard ratios for European, African, Hispanic, and Asian subsets were 4.26 [3.66-4.9], 2.4 [1.77-3.23], 4.72 [2.68-8.87], and 10.46 [2.01-101.0]. When accounting for family history and ancestry group, PHS290 remained a strong independent predictor of fatal prostate cancer. PHS290 was also associated with metastasis. PHS290 was higher, on average, among men with African ancestry. Conclusions and Relevance: PHS290 stratified US veterans of diverse ancestry for lifetime risk of metastatic or fatal prostate cancer. Predicting genetic risk of lethal prostate cancer with PHS290 might inform individualized decisions about prostate cancer screening.