PCOS, Type II diabetes and ovarian cancer risk

 描述(申请人提供)：背景：多囊卵巢综合征(PCOS)是一种以月经少和高雄激素血症为特征的复杂内分泌疾病。多囊卵巢综合征还与代谢紊乱的风险有关，包括2型糖尿病、胰岛素抵抗和代谢综合征，这些也可能影响癌症风险。通过组织学亚型检查多囊卵巢综合征、II型糖尿病和代谢综合征与卵巢癌之间的联系，可以进一步了解这些潜在联系背后的机制(S)，并有助于识别卵巢癌风险增加的女性。假设/特定目的：我们的目的是研究PCOS、II型糖尿病和这些疾病的组成部分之间的联系，以及卵巢癌的组织学亚型。我们还将研究这些情况与卵巢癌肿瘤组织标记物表达之间的关系。最后，尽管进行了有效的研究设计和分析，但混淆可能是观察性研究中的一个问题。孟德尔随机化，即从父母到后代的基因随机分类，提供了一种检查拟议暴露与结果之间的关联的方法，而不会扭曲混淆。我们计划检验以下假设：1.多囊卵巢综合征与卵巢癌风险增加有关，特别是子宫内膜样亚型。2.II型糖尿病和代谢综合征与卵巢癌风险增加有关，特别是与子宫内膜样癌和透明细胞亚型有关。3.使用孟德尔随机化方法，与II型糖尿病和多囊卵巢综合征相关的基因变异与卵巢癌风险增加有关。4.PCOS、II型糖尿病及其相关特征与表达特定组织标志物(IGF-1R、PTEN、BAF250a(ARID1A)、HOXA-10、IL8、PAX2和MAPK)的肿瘤相关。研究设计：拟议的项目将利用新英格兰病例对照研究，一项基于人群的卵巢癌研究(目标1-4)，以及卵巢癌协会联合会，汇集了13项卵巢癌病例对照研究的数据(目标1)。调查问卷数据将用于检查多囊卵巢综合征、II型糖尿病以及相关特征和卵巢癌风险。全基因组关联研究(GWAS)数据将用于孟德尔随机化分析。与多囊卵巢综合征或II型糖尿病相关的分子标志物的组织表达也将被检测。

 DESCRIPTION (provided by applicant): Background: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder condition characterized by oligomenorrhea and hyperandrogenism. PCOS is also associated with risk of metabolic disturbances including type 2 diabetes, insulin resistance, and metabolic syndrome, which may also influence cancer risk. Examining the association between PCOS, type II diabetes, and metabolic syndrome, and ovarian cancer by histologic subtype could further our understanding of the mechanism(s) behind these potential associations and help identify women at increased risk for ovarian cancer. Hypothesis/Specific Aims: Our aim is to examine the association between PCOS, type II diabetes, and components of these conditions overall and by histologic subtype of ovarian cancer. We will also examine the association between these conditions and tissue marker expression in ovarian cancer tumors. Finally, despite valid study design and analysis, confounding can be an issue in observational studies. Mendelian randomization, the random assortment of genes from parents to offspring, offers a method for examining the association between proposed exposures and outcomes without the distortion of confounding. We plan to test the following hypotheses: 1. PCOS is associated with increased ovarian cancer risk, specifically for the endometrioid subtype. 2. Type II diabetes and metabolic syndrome are associated with increased ovarian cancer risk, specifically with endometrioid and clear cell subtypes. 3. Using a Mendelian randomization approach, genetic variants associated with type II diabetes and PCOS are associated with increased ovarian cancer risk. 4. PCOS, type II diabetes, and their associated characteristics are associated with tumors expressing specific tissue markers (IGF-1R, PTEN, BAF250a (ARID1A), HOXA-10, IL8, PAX2, and MAPK). Study Design: The proposed project will utilize the New England Case-Control Study, a population based study of ovarian cancer (Aims 1-4), and the Ovarian Cancer Association Consortium, pooled data from 13 ovarian cancer case-controls studies (Aim 1). Questionnaire data will be utilized for examining PCOS, type II diabetes, and associated characteristics and ovarian cancer risk. Genome-wide association studies (GWAS) data will be used for the Mendelian randomization analyses. Tissue expression of molecular markers associated with PCOS or type II diabetes will also be examined.