Prostate cancer risk stratification by polygenic score in diabetic and non-diabetic men

Background: Type 2 diabetes mellitus (T2DM) has been inversely associated with prostate cancer (PrCa) risk. However, it remains unclear whether a polygenic risk score (PRS) for PrCa can effectively stratify risk among men with T2DM. This study aimed to assess whether a PrCa PRS could predicts PrCa risk independently of T2DM status. Methods: We analyzed data from over 140,000 men in the UK Biobank and Penn Medicine Biobank. A PrCa PRS was constructed using summary statistics from a large-scale genome-wide association study. Cox proportional hazards models were used to evaluate the association between PRS and incident PrCa, adjusting for relevant covariates and testing for interaction by T2DM status. Additionally, sex hormones and insulin-like growth factor-1 (IGF-1) levels were analyzed to explore potential mediators. Results: T2DM was associated with a reduced incidence of PrCa. IGF-1 levels were positively associated with PrCa risk in both diabetic and non-diabetic men, while sex hormone levels showed no significant association in men with T2DM. PRS was significantly associated with PrCa risk regardless of T2DM status ( P < 0.001). Men in the very high PRS category had the highest PrCa risk, particularly among those without T2DM. Adjusting for testosterone and IGF-1 levels did not attenuate the association between PRS and PrCa. Conclusions: PrCa PRS effectively stratifies prostate cancer risk in men both with and without diabetes, underscoring genetic susceptibility as a robust, independent risk factor. Given the significantly lower baseline IGF-1 levels in T2DM patients, IGF-1 might partially explain the reduced PrCa risk observed in this population.