Prostate Cancer Mortality Associated with Aggregate Polymorphisms in Androgen-Regulating Genes: The Atherosclerosis Risk in the Communities (ARIC) Study

SIMPLE SUMMARY: The growth of prostate cancer is driven by androgens through activation of the androgen receptors and its target genes in the prostate tumor tissue. Alterations in several genes involved in androgen regulation may influence the prognosis of prostate cancer, but have not been tested in a population-based study. In this epidemiological study, we confirmed that the alteration in the HSD3B1 gene that affected the progression of prostate cancer in clinical trials, is associated with increased risk of prostate cancer death in men diagnosed with metastatic disease. Additionally, we examined the cumulative effect of pre-specified alterations in the three critical androgen-regulating genes (including HSD3B1) and found that their combination predisposes to death from prostate cancer. Our findings suggest that an interplay between the androgen-regulating genes may influence the prognosis of prostate cancer and should be further examined for tailoring prostate cancer treatment. ABSTRACT: Genetic variations in androgen metabolism may influence prostate cancer (PC) prognosis. Clinical studies consistently linked PC prognosis with four single nucleotide polymorphisms (SNPs) in the critical androgen-regulating genes: 3-beta-hydroxysteroid dehydrogenase (HSD3B1) rs1047303, 5-alpha-reductase 2 (SRD5A2) rs523349, and solute carrier organic ion (SLCO2B1) rs1789693 and rs12422149. We tested the association of four androgen-regulating SNPs, individually and combined, with PC-specific mortality in the ARIC population-based prospective cohort. Men diagnosed with PC (N = 622; 79% White, 21% Black) were followed for death (N = 350) including PC death (N = 74). Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95%CI adjusting for center, age, stage, and grade at diagnosis using separate hazards for races. A priori genetic risk score (GRS) was created as the unweighted sum of risk alleles in the four pre-selected SNPs. The gain-of-function rs1047303C allele was associated PC-specific mortality among men with metastatic PC at diagnosis (HR = 4.89 per risk allele, p = 0.01). Higher GRS was associated with PC-specific mortality (per risk allele: HR = 1.26, p = 0.03). We confirmed that the gain-of-function allele in HSD3B1 rs1047303 is associated with greater PC mortality in men with metastatic disease. Additionally, our findings suggest a cumulative effect of androgen-regulating genes on PC-specific mortality; however, further validation is required.