Polygenic risk score and 20-year prostate cancer-specific mortality and survival.

Abstract

Polygenic risk scores (PRSs) strongly discriminate for prostate cancer risk at the population level. The role of these genetic scores in determining prostate cancer survival is unclear, potentially due to methodological issues. We included 19,607 men from the Malmö Diet and Cancer Study (MDCS) and the Health Professionals Follow-up Study (HPFS) and analyzed 20-year incidence and mortality (from full cohort analyses) and survival (from case-only analyses) according to a 451-variant PRS. For most of the men included, early access to prostate-specific antigen (PSA) testing was limited. In full cohort analyses, a PRS at or above the median (vs. below the median) shows a strong association with prostate cancer incidence (hazard ratio (HR) 3.02, 95% CI 2.78-3.28) and, somewhat stronger, with prostate cancer mortality (HR 3.26, 95% CI 2.63-4.04). As expected, case-only survival analyses of prostate cancer death show a similar direction (HR 1.21, 95% CI 0.98-1.50), which becomes stronger when excluding variants linked to PSA (HR 1.25, 95% CI, 1.01-1.54), in particular in the age group 65-74 years at diagnosis (HR 1.72, 95% CI 1.21-2.45). In the other age groups, HRs are close to or below 1. This indicates that standard case-only survival estimates may not accurately reflect risk across age, consistent with age-dependent selection mechanisms, and further points to an influence from disease detection. Overall, these findings support that inherited genetic risk captured by the 451-variant PRS may have an influence on prostate cancer survival. Inherited genetic factors, in particular when combined into a polygenic risk score, can be used to determine risk for prostate cancer. However, in men already diagnosed with prostate cancer, the role of such scores is unclear. In this study, we examined if a previously developed polygenic risk score for prostate cancer risk can be informative for survival. We found that for some age groups in the two included cohorts of nearly 20,000 men, a high genetic risk score was associated with worse prostate cancer survival. We also identified individual genetic factors that could play a role, although the relevance for men diagnosed today will need more research. Our study further highlights methodological concerns in studies of inherited genetic risk and cancer survival.