Estrogen and Progesterone-related Gene Variants and Colorectal Cancer Risk

描述（由申请人提供）：妇女健康倡议（WHI）试验表明，使用绝经后雌激素加黄体酮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，雌激素和黄体酮在结直肠癌发生中的作用是复杂的。然而，雌激素和黄体酮影响结直肠癌发展的潜在机制尚不清楚。应用最先进的基因分型技术和统计方法，我们将在WHI观察性研究（OS）队列中评估11个对雌激素和孕激素代谢重要的候选基因的功能变异和确定单倍型结构，并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（ESR1， ESR2和PGR）的基因，以及负责局部雌激素浓度和孕激素通过雄激素（HSD17B1, HSD17B2, HSD17B4， CYP19A1和CYP17A1）和雌激素分解代谢（CYP1A1， CYP1B1和COMT）的酶。在WHI-OS的绝经后妇女队列中，将确定总共800例结直肠癌病例及其两个匹配的对照，这些妇女的血液样本达到了基线水平，没有癌症。WHI-OS队列有大量结直肠癌确诊病例，并且在使用绝经后激素治疗和环境暴露方面具有很好的特征，因此提供了一个绝佳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。在这一应用中提出的假设是新颖的，因为雌激素和黄体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是未知的。本研究的结果将有助于阐明雌激素和黄体酮在结直肠癌发生中的作用，以及WHI试验中观察到的绝经后雌激素加黄体酮治疗与单独雌激素治疗对结直肠癌风险影响的差异，并可能提示未来干预预防结直肠癌的目标。WHI-OS队列的几个独特特点，包括前瞻性设计、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和全面的共变量信息，使该队列成为结直肠癌病因调查的宝贵和特殊资源。

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.