Association of androgen metabolism gene polymorphisms with prostate cancer risk and androgen concentrations: Results from the Prostate Cancer Prevention Trial

Abstract

Background Prostate cancer is highly influenced by androgens and genes. We investigated whether genetic polymorphisms along the androgen biosynthesis and metabolism pathways are associated with androgen concentrations or risk of prostate cancer or high-grade disease from finasteride treatment. Methods A nested case-control study from the Prostate Cancer Prevention Trial using cases drawn from men with biopsy-proven prostate cancer and biopsy-negative, frequency-matched controls was conducted to investigate the association of 51 single nucleotide polymorphisms (SNPs) in 12 genes of the androgen pathway with total, low-grade, and high-grade prostate cancer incidence and serum hormone concentrations. Results There were significant associations of genetic polymorphisms in SRD5A1 (rs3736316, rs3822430, rs1560149, rs248797, and rs472402) and SRD5A2 (rs2300700) with risk of high-grade prostate cancer in the placebo arm of the PCPT; two SNPs were significantly associated with increased risk (SRD5A1 rs472402 [OR, 1.70; 95% CI, 1.05-2.75, Ptrend=0.03]; SRD5A2 rs2300700 [OR, 1.94; 95% CI, 1.19-3.18, Ptrend=0.01]). Eleven SNPs in SRD5A1, SRD5A2, CYP1B1, and CYP3A4 were found to be associated with modifying mean serum androgen and sex hormone-binding globulin concentrations; two SNPs (SRD5A1 rs824811 and CYP1B1 rs10012, Ptrend<0.05) consistently and significantly altered all androgen concentrations. Several SNPs (rs3822430, rs2300700; CYP3A43 rs800672; CYP19 rs700519; Ptrend<0.05) were significantly associated with both circulating hormone levels and prostate cancer risk. Conclusion Germline genetic variations of androgen-related pathway genes are associated with serum androgen concentrations and risk of prostate cancer. Further studies to examine the functional consequence of novel causal variants are warranted.

Germline genetic variation in prostate susceptibility does not predict outcomes in the chemoprevention trials PCPT and SELECT

“…Genetic variations in the pathways in which the chemoprevention agents act may influence the efficacy of the agent. Finasteride acts by inhibiting the enzyme 5α reductase which is mediated by genes of the SRF5A family [31]. Polymorphisms in the SRFA genes have been reported which affect the efficacy of Finasteride [32,33].…”

Methylation of SRD5A2 promoter predicts a better outcome for castration-resistant prostate cancer patients undergoing androgen deprivation therapy

“…For instance, studies on polymorphisms in SRD5A1 and SRD5A2 have suggested its association with PCa risk and PCa recurrence [25][26][27]. However, SRD5A2 rs9282858, the common nonsynonymous single nucleotide polymorphism was found not significantly associate with PCa risk [25]. Therefore, further studies are warranted to identify how the epigenetic change of these enzymes effects on PCa.…”

Case-only Methods Identified Genetic Loci Predicting a Subgroup of Men with Reduced Risk of High-grade Prostate Cancer by Finasteride

“…Interestingly, the GG genotype for SNP rs472402 was associated with increased risk of high-grade cancer (OR ¼ 1.7; 95% CI, 1.05-2.75; ref. 19) but not with low-grade cancer, and we found that this GG genotype is also associated with a 55% reduction of high-grade cancer risk by finasteride. This SNP has recently been shown to be associated with d-amphetamine response in a genome-wide association study (22).…”

“…As the set of SNPs we analyzed were picked from candidate genes related to prostate cancer, some of the identified effect-modifying SNPs have been reported to be associated with risk of prostate cancer in previous PCPT analyses. Five of the six effect-modifying SNPs we detected in SRD5A1 (rs3736316, rs3822430, rs472402, rs1560149, and rs248797) were also significantly associated with risk of high-grade cancer in the placebo arm (19). Interestingly, the GG genotype for SNP rs472402 was associated with increased risk of high-grade cancer (OR ¼ 1.7; 95% CI, 1.05-2.75; ref.…”

“…The control selection scheme has been described previously (18), with frequency matched to cases on distributions of treatment arm, age (in 5-year age groups), and positive family history for a first-degree relative with prostate cancer. In this analysis, we retrieved genotypic data from 1,167 cases and 1,365 controls who had sufficient DNA from white blood cells (WBC) available for genotyping in various projects, which have been published previously with details in genotyping (19)(20)(21). This case-control set included additional cases who had end-of-study biopsy between 90 and 180 days after 7 years' follow-up who were not reported in the primary analysis.…”