Validation and context-dependent effects of a prostate cancer polygenic risk score in the All of Us Research Program

Polygenic risk scores (PRSs) have demonstrated strong potential for improving prostate cancer risk stratification. However, it is unknown whether the clinical utility of prostate cancer PRS vary by demographic, lifestyle, and socioeconomic factors. We validated a previously developed multi-ancestry PRS of 451 prostate cancer risk variants and evaluated context-dependent effects using genetic and clinical data from the diverse All of Us Research Program, including 7,577 cases and 90,608 controls across six genetic ancestry groups. In ancestry-stratified testing, the PRS showed strong associations with prostate cancer risk, with odds ratios (ORs) per standard deviation (SD) increase ranging from 1.61 (95% CI=1.02-2.64, P=0.05) in Middle Eastern to 2.19 (95% CI=1.98-2.42, P=2.2×10 ^-51 ) in American populations. Age-stratified analyses showed an overall reduced PRS effect with increasing age. Across modifiable lifestyle and healthcare access factors, PRS effects were larger in those with higher body mass index (OR ranging from 1.71-2.17 in underweight to obese individuals, P=0.02), in never or former smokers vs. current smokers (OR=2.06, 2.37, and 1.93, respectively, P=0.06), and in those recently accessing healthcare (OR=2.21 vs. 1.88, P=0.05), highlighting important context-specific modifiers. We did not observe context-dependent effects by other socioeconomic factors, such as income, education, and insurance. In a phenome-wide association study (PheWAS), the PRS was associated with 14 clinical outcomes, including known prostate cancer-related conditions. These findings confirm the predictive strength of the multi-ancestry prostate cancer PRS across diverse populations and underscore the importance of accounting for demographic, lifestyle, and healthcare-related contexts when applying PRS in clinical and public health settings.