Department of Cancer Prevention & Control, Roswell Park Cancer Institute, Buffalo, NY, USA.
SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
Carcinogenesis. 2018 Feb 9;39(2):125-133. doi: 10.1093/carcin/bgx144.
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.
大量的临床前数据表明，雌激素在前列腺癌的发展中具有致癌作用；然而，基于循环雌激素水平的流行病学证据在很大程度上是无效的。与循环雌激素相比，前列腺内的雌激素环境可能在前列腺癌的发生中发挥更重要的作用。我们使用前列腺癌预防试验 (PCPT) 中的嵌套病例对照设计，研究了参与雌激素合成、代谢和功能的基因的遗传变异与前列腺癌风险之间的关联。在白人中，仅研究了 13 个基因（PGR、ESR1、ESR2、CYP17A1、HSD17B1、CYP19A1、CYP1A1、CYP1B1、COMT、UGT1A6、UGT1A10、UGT2B7、UGT2B15）中的 25 个潜在功能单核苷酸多态性（SNP）。对照组（n=1380）根据年龄、PCPT 治疗组和家族史（n=1506）与病例进行频率匹配。使用逻辑回归模型，分别在安慰剂和非那雄胺组中，调整年龄和家族史，估计比值比（OR）和 95%置信区间（CI）。与前列腺癌风险相关的 SNP 因治疗组而异。这些关联似乎与循环雌激素和雄激素水平有关。CYP19A1 是唯一含有与安慰剂和非那雄胺组风险均相关的 SNP 的基因。对所有三种 CYP19A1 SNP （rs700518、rs2445765、rs700519）进行的单体型分析表明，与非风险等位基因单体型相比，风险等位基因单体型与两个治疗组中的前列腺癌风险增加相关。总之，雌激素相关基因中的 SNP 与前列腺癌风险之间的关联是复杂的，并且可能受到循环激素水平和非那雄胺治疗的影响。
