Identification Of Novel Single Nucleotide Polymorphisms (Snps) Associated With Risk And Prognosis In Patients With Castration-Resistant Prostate Cancer (Crpc)

Background: Liver metabolism plays a major role in life-long exposure to endogenous and exogenous carcinogens. We therefore explored associations between polymorphisms in genes involved in absorption, distribution, metabolism, and elimination (ADME) and the risk and prognosis of castration resistant prostate cancer (CRPC). Methods: DNA samples from 47 patients (43 Caucasians) with CRPC were genotyped using the Drug Metabolizing Enzymes and Transporters platform v1.0, which tests 1,243 genetic variations in 169 ADME genes. First, the frequency of SNPs in genes previously reported to correlate with PCa risk (CYP17, CYP1A1, NAT2, and PPARgamma) were determined and compared to controls. Second, SNP variants in all tested genes were screened for an association with survival using a Cox regression model and subsequent Kaplan-Meier plot evaluations and comparisons between groups with the log-rank test. Results: Overall 634 genotypes were ascertained. The rs743572 Tu003eC in CYP17 was associated with decreased risk of CRPC (Fisher9s exact test, P = 0.009, odds ratio 0.165, 95% confidence limits, 0.03-0.69), and we found no evidence that any other SNPs were strongly related to risk in this study. A combination of Cox model screening and graphical evaluation using Kaplan-Meier plots revealed that 5 were worthy of further consideration for survival. Of these, there was evidence that three SNPs were associated with CRPC prognosis in Caucasians (log-rank test p-values and hazard ratios): ABCB11 rs7602171 Gu003eA (P = 0.003, adjusted P = 0.006, HR 0.307, 95% CI 0.149-0.714, n = 30), GSTP1 rs1799811 Cu003eT (P = 0.001, HR 0.254, 95% CI 0.094-0.690, n = 38), and SLC5A6 rs1395 (P = 0.004, adjusted P = 0.008, HR 3.15, 95% CI 1.39-7.09, n = 35). Two other polymorphisms were considered interesting trends: ABCB4 rs2302387 Cu003eT (P = 0.039), and ABCC5 rs939339 Au003eG (P = 0.036). Conclusion: This exploratory pilot study is the first to show that polymorphisms in transporters involved in sterol disposition, ABCB11 and ABCB4, may be related to CRPC prognosis. Other potential associations were found in genes that regulate glutathione conjugation of carcinogens (GSTP1), vitamin uptake (SLC5A6), and nucleotide efflux (ABCC5). We also found evidence that CYP17 rs743572 is related to CRPC risk. Citation Format: Tristan M. Sissung, Deeken John, Crystal R. Leibrand, Douglas K. Price, Sheryl Ehrlich, Seth M. Steinberg, David J. Liewehr, William L. Dahut, William D. Figg. Identification of novel single nucleotide polymorphisms (SNPs) associated with risk and prognosis in patients with castration-resistant prostate cancer (CRPC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1794.