Estrogen Metabolism Related Genes & Endometrial Cancer

描述(申请人提供)：在这次竞争性更新中，我们建议在我们的病例对照研究中解决关于内源性类固醇性激素在子宫内膜癌发展中的作用的其他问题，该研究嵌套在三个队列中：纽约的纽约大学妇女健康研究，瑞典尤梅亚的瑞典北部健康和疾病研究，以及意大利米兰的Ordet研究。在之前的资助期间，我们发现绝经后雌激素(雌二醇、雌酮)和雄激素(睾酮、雄烯二酮，DHEAS)水平升高，患子宫内膜癌的风险增加。这是关于内源性雄激素和子宫内膜癌风险的第一个前瞻性数据。我们现在建议检查与雌激素代谢产物有关的子宫内膜癌风险，其中一些被认为比雌激素本身具有更强的遗传毒性，以及影响雌激素生物合成、活性和新陈代谢的功能多态性。这项建议中要检验的具体假设是：(1)循环中的16α-羟雌酮水平与子宫内膜癌的风险呈正相关，而2-羟雌酮与16α-羟雌酮的比例与风险呈负相关。这一目标将仅限于登记时处于绝经后的女性；(2)编码参与雌激素合成或代谢的酶(CYP17、CYP1B1、COMT)的选定基因的功能多态与子宫内膜癌的风险相关；以及(3)孕激素受体基因的特定多态与子宫内膜癌的风险相关。目前还没有关于子宫内膜癌和2-和16-羟雌酮的研究，也很少有关于雌激素相关基因多态性的研究。我们估计我们将累积444例子宫内膜癌病例和888例对照病例。我们还将通过检测它们与雌激素和雌激素代谢物循环水平的关系，进一步评估几种基因多态的功能重要性。

DESCRIPTION (provided by applicant): In this competing renewal, we propose to address additional questions on the role of endogenous steroid sex hormones in the development of endometrial cancer in our case-control study nested within three cohorts: the New York University Women's Health Study in New York, the Northern Sweden Health and Disease Study in Umea, Sweden, and the ORDET study in Milan, Italy. In the previous funding period we showed that the risk of endometrial cancer increased with increasing postmenopausal levels of estrogens (estradiol, estrone) and androgens (testosterone, androstenedione, DHEAS). These are the first prospective data on endogenous androgens and endometrial cancer risk. We now propose to examine endometrial cancer risk in relation to estrogen metabolites, some of which are thought to be more genotoxic than estrogens themselves, and to functional polymorphisms that impact estrogen biosynthesis, activity and metabolism. The specific hypotheses to be tested in this proposal are: (1) Circulating levels of 16alpha-hydroxyestrone are positively associated with risk of endometrial cancer, while the ratio of 2-hydroxyestrone to 16alpha-hydroxyestrone is inversely associated with risk. This aim will be restricted to women who were postmenopausal at enrollment; (2) Functional polymorphisms in selected genes coding for enzymes involved in estrogen synthesis or metabolism (CYP17, CYP1B 1, COMT) are associated with risk of endometrial cancer; and (3) Selected polymorphisms in the progesterone receptor gene are associated with risk of endometrial cancer. There are no studies on endometrial cancer and 2- and 16alpha-hydroxyestrone, and very few studies on estrogen-related polymorphisms. We estimate that we will accrue 444 incident cases of endometrial cancer and 888 controls. We will also further evaluate the functional importance of several gene polymorphisms by examining their associations with circulating levels of estrogens and estrogen metabolites.