Adrenal-permissive HSD3B1 genotype and prostate cancer-specific mortality among patients: Insights from the multiethnic cohort Study

Background : The HSD3B1 gene encodes an androgen synthesis enzyme critical for prostate cancer (PCa) progression. The CC genotype of a common missense variant in HSD3B1 (rs1047303) is considered adrenal-permissive, resulting in increased androgen synthesis, resistance to androgen deprivation therapy (ADT), and accelerated PCa progression. However, epidemiologic evidence linking this variant to prostate cancer-specific mortality (PCSM), particularly in diverse patient populations, remains limited. Methods : We investigated the recessive effect of the C allele (CC vs. AA or AC) on PCSM among incident PCa cases in the Multiethnic Cohort (MEC). Cause-specific Cox proportional hazards regression models were used to estimate the hazard ratios (HRs) and 95% CI confidence intervals (CIs), with age since PCa diagnosis as the time scale. Covariates included tumor stage (localized, regional, or distant), Gleason grade (high: ≥8 or low: <8), first-degree family history of PCa, the first ten principal components, and initial course of treatment (chemotherapy, radiation therapy, hormone therapy, or surgery). Analyses were conducted overall and in cases stratified by tumor stage, grade, and metastatic status. A sensitivity analysis was conducted, restricted to men who underwent hormone therapy as part of the initial treatment. Statistical significance was defined as a two-sided p-value <0.05. Results : Among the 3,216 incident PCa cases (34.7% Japanese Americans, 20.4% Latinos, 19.5% African Americans, 19.1% Whites, and 6.4% Native Hawaiians), 295 (9.2%) died due to PCa over a median follow-up of 5.9 years, and 115 (3.6%) carried the CC genotype. Compared to the AA/AC genotype, the CC genotype was associated with a suggestive 57% increased risk of PCSM (95% CI: 0.80-3.09, P=0.19). The association was stronger among patients with metastatic (HR=5.24, 95% CI: 1.01-8.48, P=0.01), advanced (HR=2.33, 95% CI: 0.67-8.08, P=0.18), or high-grade (HR=2.15, 95% CI: 0.80-5.79, P=0.13) PCa. In the hormone therapy subgroup, the CC genotype was significantly associated with increased PCSM among patients with metastatic (HR=6.79, 95% CI: 2.03-17.2, P<0.001) and advanced (HR=3.29, 95% CI: 1.10-11.7, P=0.03) disease. Conclusion : In this multiethnic population of PCa cases, the adrenal-permissive CC genotype of HSD3B1 rs1047303 variant was associated with a markedly increased risk of PCSM, particularly among patients with aggressive disease and those treated with hormone therapy. These findings suggest that HSD3B1 genotyping may have clinical utility in identifying patients at higher risk of poor outcomes and guiding personalized treatment strategies. Further studies with larger sample sizes are needed to confirm these associations and explore their implications for clinical decision-making.