Genetic Variation in Estrogen Sulfation Genes and Endometrial Cancer Risk

描述(由申请人提供)：这项申请背后的一个驱动前提是子宫内膜癌与过度接触非对立雌激素密切相关。雌激素推动细胞增殖，因此有机会积累随机的遗传错误，从而导致子宫内膜癌的进展。硫酸盐结合在雌激素的生物转化中起着重要的作用。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和基因毒性途径转移到致癌途径。另一方面，雌激素硫酸盐酶将生物上不活跃的雌激素-硫酸盐水解成活性雌激素。由UDP-葡萄糖醛酸基转移酶催化的葡萄糖醛酸化反应是雌激素代谢为非活性化合物的另一条途径。这些酶在子宫内膜中表达，并在调节局部雌激素的产生中发挥重要作用。我们假设调节雌激素结合的基因的功能多态与子宫内膜癌的风险有关。这些基因中常见的基因变异与子宫内膜癌风险的关系尚未进行全面评估。在这项应用中，我们将在两个大型前瞻性队列中嵌套的两个病例对照研究中，检查假定的功能多态和标记SULT1A1、SULT1E1、STS和UGT1A1的单核苷酸多态(SNPs)与子宫内膜癌风险的相关性，以及基因和基因环境与已建立的子宫内膜癌风险因素的交互作用：多种族队列(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的发现，并有足够的统计能力来检测与常见等位基因相关的适度影响，并探索基因和基因环境的相互作用。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SNPs，并应用严格的统计分析方法来解释多重比较问题。最后，我们的队列是独一无二的，因为他们提供了一个机会，在美国多种族、有时服务不足的人群中，研究子宫内膜癌遗传易感性和环境风险因素的变异。疾病等位基因的发现将具有重要的公共卫生意义，因为它有助于识别将从预防措施中受益最大的高危女性。

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.