Abstract
To address the concern that polygenic hazard scores for prostate cancer (PCa) might not distinguish between indolent and aggressive disease, we performed case-only analyses using a 601-variant polygenic score (PHS601). We hypothesized that among men who eventually developed PCa, those with higher PHS were more likely to develop aggressive disease. We analyzed genetic and phenotypic data from a diverse, national cohort of men diagnosed with PCa (Million Veteran Program, n = 69,901, 6413 metastatic). We used Cox proportional hazards models to examine the association of PHS601 with both age at onset of metastatic PCa (birth-to-met) and time from localized to metastatic diagnosis (localized-to-met). We performed an external validation of the case-only birth-to-met analysis in two population-based cohorts from the PRACTICAL Consortium. PHS601 was associated with both birth-to-met and localized-to-met within MVP. The HRs for men in the highest quintile of PHS601 vs. those in the lowest quintile (HR (80/20) ) were 1.74 [1.65-1.84] and 1.41 [1.31-1.41] for birth-to-met and localized-to-met, respectively. These findings were validated in two external cohorts (COSM and ProtecT). PHS601 was also associated with earlier development of metastasis. Men with high PHS601 are diagnosed with prostate cancer at a younger age and are more likely to develop metastasis.