Abstract 1274: Associations between genetic polymorphisms in genes related to estrogen metabolism and function and prostate cancer risk: results from the Prostate Cancer Prevention Trial

Abstract

Abstract Background: Substantial preclinical data corroborate the critical role of estrogen in prostate cancer development; however, epidemiological studies found no associations between circulating estrogen levels and prostate cancer risk. It was hypothesized that intraprostatic estrogen milieu may play a more important role than circulating estrogen in prostate carcinogenesis. Since it is difficult to obtain data on prostatic estrogen levels, we tested the hypothesis indirectly by investigating associations of prostate cancer risk with genetic variations of enzymes that are involved in estrogen synthesis, metabolism and function, and may affect intraprostatic estrogen milieu. Methods: A panel of 36 potentially functional single nucleotide polymorphisms (SNPs) in estrogen-related genes was assembled based on information obtained in the literature. After removing SNPs with call rate <95% (1 SNP) or minor allele frequency <3% (10 SNPs), a total of 25 SNPs in 13 genes (PGR, ESR1, ESR2, CYP17A1, HSD17B1, CYP19A1, CYP1A1, CYP1B1, COMT, UGT1A6, UGT1A10, UGT2B7, UGT2B15) were examined for associations with prostate cancer risk using data and DNA samples from 1617 cases and 1731 controls in the Prostate Cancer Prevention Trial (PCPT). Cases and controls were frequency-matched on age, treatment arm and family history. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) separately in the placebo and finasteride arms, adjusting for age, race and family history. Results were similar when restricting analysis to white men only. Results: Panels of SNPs that were significantly associated with prostate cancer risk were different according to treatment arm, showing rs1801132 in ESR1, rs700518 in CYP19A1, and rs4124874 in UGT1A6 in the placebo arm and rs2445765 in CYP19A1 and rs4680 in COMT in the finasteride arm. When stratified by circulating estrogen and androgen levels, significant associations were only observed in either the high or low category of serum hormone levels; no SNPs were significantly associated with prostate cancer risk in both categories. CYP19A1 was the only gene harboring SNPs that were significantly associated with prostate cancer risk in both the placebo (rs700518) and finasteride arms (rs2445765). In haplotype analysis using all three CYP19A1 SNPs genotyped in the study (rs700518, rs2445765 and rs700519), compared with non-risk haplotype (GCC), certain CYP19A1 haplotypes were significantly associated with increased prostate cancer risk in both arms. Conclusion: Associations between prostate cancer risk and SNPs in genes involved in estrogen metabolism and function are complicated, and markedly modified by other factors such as finasteride treatment or circulating hormone levels. Supported by grant U10CA37429, 5UM1CA182883 and P01CA108964 from the NCI. Citation Format: Li Tang, Mary Platek, Song Yao, Cathee Till, Phyllis Goodman, Catherine M. Tangen, Yue Wu, Elizabeth A. Platz, Marian L. Neuhouse, Frank Z. Stanczyk, Juergen K. Reichardt, Regina M. Santella, Ann Hsing, William D. Figg, Scott M. Lippman, Ian M. Thompson, Christine B. Ambrosone. Associations between genetic polymorphisms in genes related to estrogen metabolism and function and prostate cancer risk: results from the Prostate Cancer Prevention Trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1274. doi:10.1158/1538-7445.AM2017-1274