In this large population-based cohort analyzed using competing-risk methods, we found that only a subset of previously reported germline risk factors for aggressive PCa was independently associated with PCSM. PVs in three Tier-1 NCCN-recommended DDR genes (BRCA2, MSH6, PALB2) were strongly associated with PCSM, with approximately threefold increased risk. In contrast, seven additional Tier-2 NCCN-recommended DDR genes were associated with PCSM only when evaluated collectively, suggesting more moderate effects that are individually underpowered to detect. The common KLK3 I179T variant was also independently associated with PCSM, whereas HSD3B1 and all three evaluated PRSs were not associated with cumulative incidence of PCSM in competing-risk models. These findings demonstrate that germline susceptibility to PCa does not uniformly translate into risk of lethal disease and underscore the importance of population-based, incident case analyses when evaluating prognostic genetic markers. Our approach was intentionally clinically oriented rather than discovery-driven, prioritizing evaluation of established germline risk factors already used or recommended in clinical practice. Although genome-wide approaches may identify novel prognostic variants, they currently lack sufficient event numbers and validation datasets for robust evaluation of PCSM.
A clinically important aspect of our findings is that these associations were observed among men initially diagnosed with localized PCa, who comprised the majority of incident cases. Treatment decisions in localized disease require balancing the risk of progression against potential harms of therapy. Although definitive treatment may reduce risk of lethal progression in high-risk disease [1, 3, 4], PCa therapies have been associated with cardiometabolic complications and secondary malignancies that may contribute substantially to long-term mortality [6, 7]. Thus, identifying men at elevated inherited risk of lethal progression at the time of diagnosis could support more individualized treatment strategies, potentially reducing both undertreatment of aggressive disease and overtreatment of indolent tumors.
Our primary endpoint was PCSM to specifically capture prostate cancer–related lethality, as all-cause mortality may dilute associations driven by tumor biology due to competing non–cancer deaths. Evaluation of overall mortality, particularly in the context of treatment-related harms, represents a complementary but distinct clinical question. Because germline variants are present at or before diagnosis and remain stable over time, they represent a uniquely early and durable source of prognostic information.
The magnitude of risk separation observed in our study further supports potential clinical relevance. Carriers of Tier-1 PVs reached the cohort-wide median cumulative incidence of PCSM nearly eight years earlier than non-carriers, and individuals carrying both Tier-1 variants and KLK3 I179T exhibited an even larger separation. Although these differences are descriptive and not causal estimates, they provide a clinically interpretable context for urologists. For context, widely used tumor-based prognostic biomarkers such as Decipher have been shown to stratify metastatic or PCa-specific mortality risk over similar multi-year time horizons [33]. Importantly, expanding beyond Tier-1 genes to include Tier-2 genes and KLK3 substantially increased the proportion of patients classified as high genetic risk, enhancing potential applicability in clinical settings.
Our findings also clarify the role of PRSs in prognostic assessment. Despite consistent associations of PRSs with PCa susceptibility [24,25,26,27], none was associated with cumulative incidence of PCSM in Fine–Gray models. In cause-specific Cox analyses, some PRSs were associated with reduced instantaneous hazards of PCSM, likely reflecting earlier age at diagnosis rather than reduced lethality. These results suggest that currently available PRSs primarily shift the timing of PCa diagnosis rather than materially influencing disease-specific mortality after diagnosis. This distinction highlights the importance of using competing-risk frameworks when evaluating prognostic biomarkers in aging populations with substantial non–PCa mortality.
An important methodological consideration is the grouping of DDR genes into Tier-1 and Tier-2 categories. Tier-1 genes were defined by statistically robust individual associations with PCSM, whereas Tier-2 genes were grouped based on shared biological function in homologous recombination and mismatch repair pathways and their inclusion in NCCN-recommended germline testing panels. This pathway-level aggregation reflects a burden-testing approach commonly applied to rare variants and was intended to address limited statistical power for individually infrequent PVs rather than to create data-driven groupings.
Gene-specific findings were largely consistent with prior literature for BRCA2 but differed for several other genes [11,12,13,14,15,16,17,18,19]. Although ATM and CHEK2 have been implicated in aggressive PCa in selected cohorts [9, 13,14,15,16, 18, 19], their associations with PCSM in this population-based setting were attenuated and not statistically significant after correction for multiple testing. Notably, effect estimates were directionally consistent with prior reports, suggesting that limited statistical power for rare variants may contribute to discrepancies. Conversely, MSH6 and PALB2 demonstrated significant associations with PCSM in our cohort, supporting a broader role for mismatch repair and homologous recombination pathways in lethal progression. These findings emphasize the value of large, unselected cohorts with incident cases and competing-risk analysis to reduce biases related to case selection and outcome definition.
The association between KLK3 I179T and PCSM is notable given its reproducibility across large cohorts and the absence of its inclusion in current guideline-recommended germline panels [20, 21]. In addition to its well-established associations with PSA levels and PCa detection, functional studies suggest that this missense variant alters PSA enzymatic activity, supporting a biologically plausible role in tumor progression rather than detection bias alone.
In contrast, HSD3B1 was not associated with PCSM in our cohort. Prior studies suggest its adverse prognostic impact may be most pronounced in men receiving ADT [21,22,23, 34,35,36,37,38,39], which was not systematically captured in this population-based dataset.
Finally, although MRE11A demonstrated only nominal association, its established role in DNA double-strand break repair and prior links to metastatic PCa suggest it warrants further investigation in larger, harmonized cohorts [40].
Several limitations merit consideration. First, detailed clinicopathologic variables at diagnosis were incompletely captured in the UKB, limiting evaluation of incremental prognostic value beyond tumor characteristics. Nevertheless, our focus on PCSM, a robust and clinically meaningful endpoint, and the use of age as the underlying time scale mitigate some concerns related to unmeasured baseline heterogeneity. Second, PCSM was ascertained using death registry records based on ICD-coded death certificates, which may be subject to some misclassification. However, cause-specific mortality derived from national registries is generally considered reliable for major disease categories such as cancer, and the use of competing-risk methods helps mitigate potential bias. Third, the cohort was predominantly of European ancestry, and analyses among minority populations were underpowered. Future studies in more diverse cohorts will be essential to confirm the generalizability of our findings and to address disparities in PCa outcomes. Forth, despite the large overall sample, statistical power remained limited for very rare PVs with moderate effect sizes. Longer follow-up and pooled analyses across diverse cohorts will be necessary to refine risk estimates and evaluate ancestry-specific effects.
In conclusion, in this large population-based cohort, a subset of germline genetic risk factors, particularly rare PVs in key DDR genes and the common KLK3 I179T variant, was significantly associated with PCSM. These findings demonstrate that not all genetic risk factors for PCa susceptibility convey prognostic value and highlight the potential role of selected germline markers in refining risk stratification and guiding treatment decision-making at the time of diagnosis.
