Germline genetic risk and prostate cancer-specific mortality in a population-based incident cohort.

Multiple germline variants are associated with prostate cancer (PCa) susceptibility and aggressive features; however, their value for predicting prostate cancer-specific mortality (PCSM) at the time of diagnosis remains uncertain, particularly among men with clinically localized disease. We evaluated associations between germline risk factors and PCSM among 14,644 men with incident PCa in the UK Biobank. Associations between PCSM and reported germline risk factors, including 11 genes recommended by the National Comprehensive Cancer Network (NCCN), nine other candidate genes, two common variants [KLK3 (I179T) and HSD3B1 (1245 A > C)], and three polygenic risk scores (PRSs), were tested using Fine-Gray competing-risk models accounting for non-PCa mortality. During a median follow-up of 6.73 years after diagnosis, 1581 men (10.8%) died from PCa. PVs in three NCCN-recommended DNA damage-repair genes (BRCA2, MSH6, PALB2) were individually associated with increased PCSM and were defined as Tier-1. Aggregated PVs in seven additional NCCN-recommended DDR genes (Tier-2) and the KLK3 I179T variant were also independently associated with PCSM. In contrast, HOXB13, nine other candidate genes, HSD3B1, and all three PRSs were not associated with cumulative PCSM risk. Overall, 14.45% of men carried Tier-1 or Tier-2 PVs and/or KLK3 I179T and experienced significantly earlier PCa-specific mortality. Importantly, associations remained significant among men without metastatic disease at diagnosis. Reported inherited susceptibility to PCa does not uniformly confer risk of lethal progression. Germline PVs in NCCN-recommended DDR genes and the KLK3 I179T variant identify a subset of men at elevated risk of PCSM, including those with apparently localized disease. These findings support consideration of selected germline markers for prognostic risk stratification at diagnosis to inform individualized management decisions.