Polymorphisms in genes of the steroid receptor superfamily modify postmenopausal breast cancer risk associated with menopausal hormone therapy
Polymorphisms in genes of the steroid receptor superfamily modify postmenopausal breast cancer risk associated with menopausal hormone therapy
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DOI：
10.1002/ijc.24892
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发表时间：
2010-06-15
影响因子：
6.4
通讯作者：
Ko, Yon-Dschun
中科院分区：
文献类型：
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作者：
Abbas, Sascha;Beckmann, Lars;Ko, Yon-Dschun
绝经后妇女的月经激素治疗（HT）与乳腺癌风险增加有关。核受体参与类固醇激素和外源性物质介导的信号转导，在基因表达调控中起着重要作用。因此，这些基因的变异可能会影响HT相关的乳腺癌风险。我们调查了来自2项德国人群病例对照研究的3，149名绝经后乳腺癌患者和5，489名对照。根据ESR1、ESR2、PGR、PXR和AR中已知或推定的功能相关性选择33个多态性进行基因分型。采用条件Logistic回归分析评估多态性和雌孕激素治疗持续时间以及雌激素单药治疗与乳腺癌风险之间的乘法统计相互作用，假设对数加性和共显性遗传模式。我们观察到携带短AR_（CAG）等位基因（≥ 22个重复）的妇女的风险增加（p（交互作用）= 0.03）。此外，2个PXR多态性显著改变了与联合治疗使用相关的风险，降低了次要PXR_rs6785049_G和PXR_rs1054191_A等位基因携带者的风险效应（p（相互作用）分别= 0.04和0.05）。ESR1和ESR2的变异改变了与雌激素单药治疗相关的风险。在主要ESR1_rs910416_T等位基因的纯合子（p（相互作用）< 0.01）和次要ESR2_rs1271572_T、主要ESR2_rs4986938_G和次要ESR2_rs928554_G等位基因的纯合子（p（相互作用）分别= 0.02、0.05、0.02）中观察到更高的风险。经多重检验校正后，ESR1_rs910416和AR_（CAG）n多态性对风险效应的修正仍显着。我们的结论是，核受体基因的遗传变异可能会改变HT相关的绝经后乳腺癌的风险。
Menopausal hormone therapy (HT) is associated with increased breast cancer risk among postmenopausal women. Nuclear receptors are involved in steroid hormone- and xenobiotic-mediated signal transduction playing a crucial rote in regulating gene expression. Therefore, variations within these genes may influence HT-associated breast cancer risk. We investigated 3,149 postmenopausal breast cancer patients and 5,489 controls from 2 German population-based case-control studies. Thirty-three polymorphisms selected on the basis of known or putative functional relevance located in ESR1, ESR2, PGR, PXR and AR were genotyped. Conditional logistic regression was used to assess multiplicative statistical interaction between polymorphisms and duration of estrogen progestagen therapy and of estrogen monotherapy with regard to breast cancer risk assuming log-additive and codominant modes of inheritance. We observed an increased risk for women carrying short AR_(CAG) alleles of = 22 repeats) (p(interaction) = 0.03). Additionally, risk associated with combination therapy use was significantly modified by 2 PXR polymorphisms with reduction of risk effects in carriers of the minor PXR_rs6785049_G and PXR_rs1054191_A alleles (p(interaction) = 0.04 and 0.05, respectively). Variants in both ESR1 and ESR2 modified risk associated with estrogen monotherapy use. Higher risk were observed in homozygotes for the major ESR1_rs910416_T allele (p(interaction) < 0.01) and in homozygotes for the minor ESR2_rs1271572_T, major ESR2_rs4986938_G and minor ESR2_rs928554_G alleles (p(interaction) = 0.02, 0.05, 0.02, respectively). Risk effect modification by ESR1_rs910416 and AR_(CAG)n polymorphisms remained significant after correction for multiple testing. We conclude that genetic variants in nuclear receptor genes may modify HT-associated postmenopausal breast cancer risk.