Estrogen and Progesterone-related Gene Variants and Colorectal Cancer Risk

雌激素和孕激素相关基因变异与结直肠癌风险

• 批准号: 7136486
• 负责人: SHUMIN ZHANG
• 金额: $ 30.25万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7136486
• 关键词: alleles; cancer risk; clinical research; colorectal neoplasms; estrogens; genes; progesterone

DESCRIPTION (provided by applicant): The Women's Health Initiative (WHI) trial has demonstrated that use of postmenopausal estrogen plus progestin therapy reduces risk of colorectal cancer in women, but use of estrogen alone among women with prior hysterectomy has no effect. These data suggest a complex effect of estrogen and progesterone on colorectal carcinogenesis. However, the underlying mechanisms by which estrogen and progesterone affect the development of colorectal cancer are poorly understood. Applying state-of-the-art genotyping technology and statistical methods, we will evaluate functional variants and determine the structure of haplotypes in 11 candidate genes important to estrogen and progesterone metabolism, and investigate their relationships with risk of colorectal cancer in the WHI observational study (OS) cohort, an ethnically diverse population. Specific studies will focus on genes encoding estrogen and progesterone receptors (ESR1, ESR2, and PGR) and enzymes responsible for local estrogen concentrations and the conversion of progesterone to estrogens via androgens (HSD17B1, HSD17B2, HSD17B4, CYP19A1, and CYP17A1) and for estrogen catabolism (CYP1A1, CYP1B1, and COMT). A total of 800 incident colorectal cancer cases and their two matched controls will be identified in the WHI-OS cohort of postmenopausal women with achieved blood samples and free of cancer at baseline. The WHI-OS cohort has a large number of confirmed cases of colorectal cancer and is well characterized with respect to use of postmenopausal hormone therapy and environmental exposures, thus providing an extraordinary opportunity to examine the main effects of gene variants and their interactions with use of combination hormone therapy vs. estrogen alone in relation to colorectal cancer risk. We also will explore interactions among these candidate genes. Hypotheses proposed in this application are novel, as the relations between estrogen and progesterone-related gene variants and risk of colorectal cancer are largely unexplored. Findings from this proposed study will help elucidate the roles of estrogen and progesterone in colorectal carcinogenesis, the differences between the effects of postmenopausal estrogen plus progestin therapy vs. estrogen alone on colorectal cancer risk observed in the WHI trial, and may suggest future targets for interventions to prevent colorectal cancer. Several unique features of the WHI-OS cohort, including its prospective design, diverse ethnic and social composition, large sample size, long duration, high follow-up rates, availability of stored blood specimens, and comprehensive covariate information, make this cohort a valuable and exceptional resource for the etiologic investigation of colorectal cancer.

描述（由申请人提供）：妇女健康倡议（WHI）试验表明，绝经后雌激素联合孕激素治疗可降低妇女患结直肠癌的风险，但在既往子宫切除术的妇女中单独使用雌激素没有效果。这些数据表明，雌激素和孕激素对结直肠癌发生的复杂作用。然而，雌激素和孕激素影响结直肠癌发展的潜在机制知之甚少。应用最先进的基因分型技术和统计学方法，我们将评估功能变异并确定对雌激素和孕激素代谢重要的11个候选基因的单倍型结构，并在WHI观察性研究（OS）队列（一个种族多样化的人群）中研究它们与结直肠癌风险的关系。具体的研究将集中在编码雌激素和孕激素受体（ESR 1，ESR 2和PGR）的基因和负责局部雌激素浓度和通过雄激素将孕激素转化为雌激素（HSD 17 B1，HSD 17 B2，HSD 17 B4，CYP 19 A1和CYP 17 A1）和雌激素催化剂（CYP 1A 1，CYP 1B 1和COMT）的酶。在基线时获得血液样本且无癌症的绝经后女性WHI-OS队列中，将确定共计800例新发结直肠癌病例及其2例匹配对照。WHI-OS队列有大量确诊的结直肠癌病例，并且在使用绝经后激素治疗和环境暴露方面得到了很好的表征，因此提供了一个非凡的机会来检查基因变异的主要影响及其与使用联合激素治疗与单独雌激素治疗的相互作用与结直肠癌风险的关系。我们还将探索这些候选基因之间的相互作用。本申请中提出的假设是新颖的，因为雌激素和孕酮相关基因变异与结直肠癌风险之间的关系在很大程度上尚未探索。这项拟议研究的结果将有助于阐明雌激素和孕激素在结直肠癌发生中的作用，绝经后雌激素加孕酮治疗与单独雌激素治疗对WHI试验中观察到的结直肠癌风险的影响之间的差异，并可能为预防结直肠癌的干预措施提供未来的目标。WHI-OS队列的几个独特特征，包括其前瞻性设计，多样化的种族和社会组成，大样本量，长时间，高随访率，储存血液标本的可用性，以及全面的协变量信息，使该队列成为结直肠癌病因学研究的宝贵和特殊资源。