Estrogen receptor polymorphisms and the risk of endometrial cancer
Estrogen receptor polymorphisms and the risk of endometrial cancer
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DOI：
10.1111/j.1471-0528.2009.02185.x
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发表时间：
2009-07-01
影响因子：
5.8
通讯作者：
Scott, R. J.
中科院分区：
文献类型：
--
作者：
Ashton, K. A.;Proietto, A.;Scott, R. J.
有证据表明雌激素及其代谢产物与子宫内膜癌的发病有关。由于雌激素通过雌激素受体ESR1和ESR2介导其作用，本研究的目的是确定这两个基因的6个单核苷酸多态性（snp）在子宫内膜癌患者群体中是否与健康匹配的对照人群相比过度代表，从而将这些基因的差异与子宫内膜癌联系起来。该研究是一项病例对照调查，其规模足以检测到两倍的风险增加，假设存在显性遗传模型，P = 0.05，功率为80%。研究和对照种群均来自澳大利亚新南威尔士州亨特-新英格兰地区，收集时间为1992年至2005年。该研究包括191名子宫内膜癌患者和291名性别和年龄相匹配的健康对照组。采用PCR限制性内切片段长度多态性分析和实时荧光定量PCR对ESR1中的2个snp和ESR2中的4个snp进行基因分型。使用无条件逻辑回归计算优势比，SIMHAP用于单倍型分析，调整潜在的子宫内膜癌危险因素。采用Kaplan-Meier生存分析、Cox回归和t检验检验患者诊断子宫内膜癌的年龄和基因型。与对照组相比，子宫内膜癌人群中ESR1和ESR2多态性的过度表达表明参与了疾病的发生和/或进展。两个ESR1 （rs2234693和rs9340799）和两个ESR2 （rs1255998和rs944050）多态性与子宫内膜癌风险增加相关。在对危险因素进行调整后，与ESR1和ESR2多态性（rs2234693、rs1255998和rs944050）的关联仍然非常显著。单倍型分析显示，携带ESR1单倍型（变异等位基因rs2234693和rs9340799）和ESR2单倍型（变异等位基因rs1255998和野生型等位基因rs944050、rs4986938和rs1256049）的人患乳腺癌的风险增加（OR分别为1.862,P = 0.013和1.918,P = 0.046）。携带两种风险单倍型的女性的风险更大（OR 5.041, P = 0.007）。我们的数据表明，ESR1 （rs2234693和rs9340799）和ESR2 （rs1255998和rs944050）多态性可能与发生子宫内膜癌的风险增加有关。
There is evidence that estrogens and some of their metabolites are involved in endometrial cancer pathogenesis. As estrogens mediate their effects via the estrogen receptors, ESR1 and ESR2, the objective of this investigation was to determine whether six single nucleotide polymorphisms (SNPs) in these two genes were over-represented in a population of endometrial cancer patients compared with a healthy matched control population, thereby associating differences in these genes with endometrial cancer.The study is a case-control investigation large enough to detect a two-fold increased risk, assuming a dominant genetic model, with P = 0.05 and 80% power.The study and control populations were all from the Hunter-New England region of New South Wales, Australia collected between the years 1992 and 2005.The study consisted of 191 endometrial cancer patients and 291 healthy controls matched for gender and age.Two SNPs in ESR1 and four SNPs in ESR2 were genotyped using PCR-based restriction fragment length polymorphism analysis and real-time PCR. Odds ratios were calculated using unconditional logistic regression and SIMHAP was used for haplotype analysis, adjusting for potential endometrial cancer risk factors. Kaplan-Meier survival analysis, Cox regression and t tests were used to examine the patient's age of diagnosis of endometrial cancer and genotype.Over-representation of ESR1 and ESR2 polymorphisms in the endometrial cancer population compared with the control population indicates an involvement in the development and/or progression of disease.Two ESR1 (rs2234693 and rs9340799) and two ESR2 (rs1255998 and rs944050) polymorphisms were associated with an increased risk of endometrial cancer. Following adjustment for risk factors, the association with the ESR1 and ESR2 polymorphisms (rs2234693, rs1255998 and rs944050) remained highly significant. Haplotype analysis revealed that carriers of the ESR1 haplotype (variant alleles; rs2234693 and rs9340799) and the ESR2 haplotype (variant allele; rs1255998 and wild-type alleles; rs944050, rs4986938 and rs1256049) were at an increased risk (OR 1.862, P = 0.013 and OR 1.918, P = 0.046 respectively). This risk was even greater in women carrying both risk haplotypes (OR 5.041, P = 0.007).Our data suggest that the ESR1 (rs2234693 and rs9340799) and the ESR2 (rs1255998 and rs944050) polymorphisms may be associated with an increased risk of developing endometrial cancer.