Association of polymorphisms in androgen production, uptake, and conversion chain (APUC) genes with mortality of prostate cancer patients.

Abstract

5528 Background: Genes involved in APUC may affect prognosis in PC. We tested the association of four SNPs involved in the APUC pathway: hydroxy-delta-5-steroid dehydrogenase, 3 beta-and steroid delta-isomerase 1 ( HSD3B1), 5α reductase enzyme ( SRD5A), and solute carrier organic ion ( SLCO2B1) with all-cause and PC mortality 596 in the Atherosclerosis Risk in Communities (ARIC) study. Methods: Between 1987 & 2015 596 men were diagnosed with PC. Median age at diagnosis was 70 (range 53-86) years; 21% of all PC patients were African American. After diagnosis, follow-up was median 8.4 years (max 26.7 years) until PrC death (N = 60), death from any cause (N = 253), or end of 2015. SNPs were genotyped using the Affymetrix Genome-Wide Human SNP Array 6.0 and imputed to the 1000 Genomes Phase 3 reference panel. To examine survival, we used Kaplan-Meier curves and Cox proportional hazards regression. Hazard ratios (HR) and 95% confidence intervals (CI) were adjusted for age, field center, stage and grade at diagnosis. We also controlled for confounding by ancestry by adjusting for genetic principal components. The analyses were conducted in all PrCa patients and in Whites PrCa patients only. Polymorphisms tested included rs1047303 (A = > C, also called 1245C); rs523349 (C = > G); and rs1789693 (A = > T) and rs12422149 (G = > A), located in the aforementioned genes. Results: The A allele for SLCO2B1 rs1789693 (A = > T) was significantly associated with an increased risk of PC mortality (versus T): multivariable-adjusted HRs (95%CI) were (2.06, 1.14-3.74; p = 0.02) and all-cause mortality (1.29, 1.00-1.66; p = 0.05) among Whites. The associations were similar when Whites and African-Americans were combined and when accounting for ancestry. The C allele for HSD3B1 rs1047303 (C = > A) was not statistically significantly associated with either PC or all-cause mortality in the whole cohort (which included localized disease), although HRs were increased for men diagnosed with stage 4 disease (n = 35) in both additive and dominant models. For carriers of the C allele (gain of function) versus AA, HRs were 5.32 (1.16-24.33; p = 0.03) and 6.13 (1.51-24.86; p = 0.01) for PC and all-cause mortality, respectively. All associations with SRDA2 (rs12422149) and SLCO2B1 (rs12422149) were not significant. Conclusions: The gain of function allele in HSD3B1 rs1047303 (1245C) was associated with increased PC and all-cause mortality in men diagnosed with metastatic PC, paralleling prior findings. Associations with SLCO2B1 SNP rs1789693 require validation in larger studies.