Genetic Susceptibility to Endometrial Cancer

描述（由申请人提供）：过量的雌激素暴露而不受孕激素抵抗与子宫内膜癌风险增加有关。参与雌激素代谢的基因多态性影响这些激素的水平，并可能与子宫内膜癌的风险改变有关;然而，迄今为止很少有研究进行。子宫内膜癌特别值得研究，因为它是雌激素相关性最强的肿瘤，因此代谢基因的适度影响可能更容易检测。为此，我们建议继续研究所选候选基因的多态性及其与子宫内膜癌的关系，使用一个大型的特征明确的队列，护士健康研究（NHS），并增加第二个大型队列，妇女健康研究（WHS）。第二个队列的加入将大大增加我们评估代谢雌二醇及其受体的基因多态性是否预测未来子宫内膜癌风险的能力。我们将通过将这些变体与血浆激素水平相关联来评估NHS中变体等位基因的功能意义。我们将评估星星、CYP 11 A1、17 aHSD 4型和3a-HSD 1型和2型的功能多态性和单倍型。SHBG、ESR 1和AR与子宫内膜癌风险相关。我们将试图复制我们观察到的子宫内膜癌风险与CYP 17和CYP 19之间的关联。最后，我们将量化与子宫内膜癌的相关性，并测试这些相关性是否被已确定的子宫内膜癌风险因素如体重指数和外源性激素使用所改变。我们的研究将是为数不多的能够在两个大型定义队列中前瞻性研究这些问题的研究之一，这些队列完全确定了事件病例和其他子宫内膜癌风险因素的全面前瞻性信息。随着WHS的增加，我们总共将有955例浸润性子宫内膜癌病例。对于大多数感兴趣的基因型的主效应，我们将有>85%的把握度来检测相对风险1.50或更大。

DESCRIPTION (provided by applicant): Excess estrogen exposure unopposed by progesterone is associated with increased risk of endometrial cancer. Polymorphisms in genes involved in estrogen metabolism influence the levels of these hormones and may be associated with an altered risk of endometrial cancer; however few studies have been conducted to date. Endometrial cancer is particularly worth studying because it is the most estrogen associated tumor and thus modest effects of hormone-metabolizing genes may be more easily detectable. To this end, we propose to continue to study polymorphisms in selected candidate genes and their relation to endometrial cancer using a large well-characterized cohort, the Nurses' Health Study (NHS), and to add a second large cohort, the Women's Health Study (WHS). The addition of this second cohort will substantially increase our power to assess whether polymorphisms in genes that metabolize estradiol and their receptors are predictive of future endometrial cancer risk. We will assess the functional significance of the variant alleles in the NHS by correlating these variants with plasma hormone levels. We will assess whether functional polymorphisms and haplotypes in StAR, CYP11A1, 17aHSD type 4, and 3a-HSD type 1 and 2. SHBG, ESR1 and AR are associated with endometrial cancer risk. We will seek to replicate associations we observed between endometrial cancer risk, and CYP17 and CYP19. Finally, we will quantify the association with endometrial cancer and test whether these associations are modified by established endometrial cancer risk factors such as body mass index and exogenous hormone use. Our study will be among the few studies able to prospectively examine these issues in two large defined cohorts with complete ascertainment of incident cases and comprehensive prospective information on other endometrial cancer risk factors. With the addition of the WHS we will have a total of 955 invasive endometrial cancer cases. We will have >85% power to detect a relative risk 1.50 or greater for the main effects of most of the genotypes of interest.