Substantial preclinical data suggest estrogen's carcinogenic role in prostate cancer development; however, epidemiological evidence based on circulating estrogen levels is largely null. Compared with circulating estrogen, the intraprostatic estrogen milieu may play a more important role in prostate carcinogenesis. Using a nested case-control design in the Prostate Cancer Prevention Trial (PCPT), we examined associations of genetic variants of genes that are involved in estrogen synthesis, metabolism and function with prostate cancer risk. A total of 25 potentially functional single nucleotide polymorphisms (SNPs) in 13 genes (PGR, ESR1, ESR2, CYP17A1, HSD17B1, CYP19A1, CYP1A1, CYP1B1,COMT, UGT1A6, UGT1A10, UGT2B7, UGT2B15) were examined in whites only. Controls (n=1380) were frequency matched to cases on age, PCPT treatment arm, and family history (n=1506). Logistic regression models adjusted for age and family history were used to estimate odds ratios (OR) and 95% confidence intervals (CI) separately in the placebo and finasteride arms. SNPs associated with prostate cancer risk differed by treatment arm. The associations appeared to be modified by circulating estrogen and androgen levels. CYP19A1 was the only gene harboring SNPs that were significantly associated with risk in both the placebo and finasteride arms. Haplotype analysis with all three CYP19A1 SNPs genotyped (rs700518, rs2445765, rs700519) showed that risk-allele haplotypes are associated with the increased prostate cancer risk in both arms when comparing with the non-risk allele haplotype. In conclusion, associations between SNPs in estrogen-related genes and prostate cancer risk are complex and may be modified by circulating hormone levels and finasteride treatment.
Carcinogenesis. 2017 Dec 08 [Epub ahead of print]
Li Tang, Mary E Platek, Song Yao, Cathee Till, Phyllis J Goodman, Catherine M Tangen, Yue Wu, Elizabeth A Platz, Marian L Neuhouser, Frank Z Stanczyk, Juergen K V Reichardt, Regina M Santella, Ann Hsing, William D Figg, Scott M Lippman, Ian M Thompson, Christine B Ambrosone
Roswell Park Cancer Institute, Buffalo, New York., Fred Hutchinson Cancer Research Center, Seattle, Washington., Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland., University of Southern California, Los Angeles, California., Yachay Tech University, San Miguel de Urcuquí, Ecuador., Columbia University, New York, New York., Stanford University School of Medicine, Stanford, California., National Cancer Institute, Bethesda, Maryland., UC San Diego Moores Cancer Center, San Diego, California., University of Texas Health Science Center at San Antonio, San Antonio, Texas.