Genetic Variation in Estrogen Sulfation Genes and Endometrial Cancer Risk

描述（由申请人提供）：本申请背后的驱动前提是子宫内膜癌与过度暴露于非对抗性雌激素密切相关。雌激素驱动细胞增殖，因此有机会积累随机遗传错误，可导致子宫内膜癌的进展。硫酸结合在雌激素的生物转化中起着重要作用。雌激素磺基转移酶催化生物活性雌激素转化为非活性雌激素硫酸盐，从而将这些激素从受体介导的和遗传毒性的途径“转移”，导致致癌作用。另一方面，雌激素硫酸酯酶将生物学上无活性的雌激素硫酸酯水解为活性雌激素。由UDP-葡萄糖醛酸转移酶催化的葡萄糖醛酸化是雌激素代谢为非活性化合物的另一种途径。这些酶在子宫内膜中表达，在调节局部雌激素产生中起重要作用。我们假设调节雌激素结合的基因的功能多态性与子宫内膜癌风险相关。尚未对这些基因中常见的遗传变异与子宫内膜癌风险的关系进行全面评估。在本申请中，我们将在两个大型前瞻性队列中嵌套的两项病例对照研究中，检查SULT 1A 1、SULT 1 E1、STS和UGT 1A 1中推定的功能多态性和标记单核苷酸多态性（SNP）与子宫内膜癌风险之间的关联，沿着基因外和基因外环境与已确定的子宫内膜癌风险因素的相互作用：多种族队列研究（500例和1,000例对照）和加州教师研究（400例和800例对照）。通过结合这些研究，我们将能够交叉验证和复制提示性结果，并有足够的统计能力来检测与常见等位基因相关的适度效应，并探索基因与基因和基因与环境的相互作用。在这里，我们将利用新的高通量多重基因分型技术来评估许多SNP，并应用严格的统计分析方法来解释多重比较问题。最后，我们的队列是独特的，因为它们提供了一个机会，研究子宫内膜癌遗传易感性的变化和环境风险因素在多种族，有时在美国服务不足的人群疾病等位基因的发现将有一个重要的公共卫生意义，因为它有助于确定高危妇女谁将受益于预防措施最多。

DESCRIPTION (provided by applicant): A driving premise behind this application is that endometrial cancer is strongly related to excessive exposure to unopposed estrogens. Estrogens drive cell proliferation, and thus the opportunity for the accumulation of random genetic errors that can lead to progression of endometrial cancer. Sulfate conjugation plays an important role in the biotransformation of estrogens. Estrogen sulfotransferases catalyze the conversion of biologically active estrogens to inactive estrogen sulfates, thereby "diverting" these hormones from both receptor mediated and genotoxic pathways leading to carcinogenesis. Estrogen sulfatases, on the other hand, hydrolyze biologically inactive estrogen-sulfate to active estrogens. Glucuronidation, catalyzed by UDP-glucuronosyl transferase enzymes, is another pathway through which estrogens can be metabolized to inactive compounds. These enzymes are expressed in the endometrium and play an important role in the regulation of local estrogenic production. We hypothesize that functional polymorphisms in genes regulating estrogen conjugation are associated with endometrial cancer risk. A comprehensive evaluation of common genetic variation in these genes in relation to endometrial cancer risk has not been conducted. In this application, we will examine associations between putative functional polymorphisms and tagging single nucleotide polymorphisms (SNPs) in SULT1A1, SULT1E1, STS and UGT1A1 with endometrial cancer risk, along with genexgene and genexenvironment interactions with established endometrial cancer risk factors, in two case-control studies nested within two large prospective cohorts: the Multiethnic Cohort (500 cases and 1,000 controls) and the California Teachers Study (400 cases and 800 controls). By combining these studies we will be able to cross-validate and replicate suggestive findings, and have an adequate statistical power to detect modest effects associated with common alleles and to explore genexgene and genexenvironment interactions. Here we will utilize novel high-throughput multiplexing genotyping technology for evaluating many SNPs and apply a rigorous statistical analytic method to account for multiple comparison issue. Finally, our cohorts are unique because they provide an opportunity to study variations in genetic susceptibility to endometrial cancer and environmental risk factors in multiethnic and sometimes underserved populations in the U.S. The discovery of disease alleles would have an important public health implication as it helps identify high-risk women who would benefit the most from prevention measures.