A Comprehensive Analysis of Genetic Variation in DNA Repair Genes in Relation to

描述（由申请方提供）：过量暴露于内源性和外源性雌激素源可增强子宫内膜中的细胞分裂，这被认为可增加体细胞突变发生的速率，并在随后的有丝分裂中固定，并在癌症发展中起起始事件的作用。已经发展了多种高度保守的机制来识别和科普来自内源性和外源性来源的DNA的持续损伤，并保持基因组的完整性。许多人类癌症综合征是由DNA修复基因中罕见的种系突变引起的，这些突变导致正常DNA修复能力的缺陷。其中一种由错配修复基因突变引起的综合征是遗传性非息肉病性结直肠癌。子宫内膜癌是这种家族综合征的常见表型，直接涉及这种疾病的发病机制中的DNA修复能力。迄今为止，低渗透等位基因在错配修复或其他DNA损伤修复或反应途径中的作用与子宫内膜癌风险的关系尚未得到彻底研究。目前的项目建立在现有资源的基础上，有效和全面地研究了DNA修复相关途径中61个候选基因中常见遗传变异对子宫内膜癌风险的重要性。在过去的一年中，我们构建了一个最佳的“标签”SNP阵列，该阵列使用Illumina基因分型技术设计，为多个种族-民族人群中这些候选基因的常见遗传变异提供了高度的可预测性。在本申请中，我们将利用前瞻性收集的生物标本、危险因素和结局数据，这些数据来自多种族队列研究中嵌套的两项已建立的子宫内膜癌病例对照研究（病例组，n = 542;对照组，n = 1，234）和加州教师研究（例，n = 580;对照组，n = 1，160），以评估这些选择的标签SNP之间的关联（大约1,200）和所有已知的错义变异（大约300）在这些基因与子宫内膜癌的风险。本研究将使用新型高通量基因分型技术以及严格的统计分析方法来解释多个假设检验，并允许在这些队列中重复和交叉验证结果。准确识别高风险亚组的能力可能对子宫内膜癌预防以及针对靶向药物开发的先进研究产生深远影响。

DESCRIPTION (provided by applicant): Excess exposure to endogenous and exogenous sources of estrogen heightens cell division in the endometrium which is thought to increase the rate at which somatic mutations occur and become fixed in subsequent mitoses, and serve as initiating events in the development of cancer. Multiple highly conserved mechanisms have evolved to identify and cope with constant insults on DNA from endogenous and exogenous sources and to maintain genomic integrity. Many human cancer syndromes are caused by rare germline mutations in DNA repair genes that result in deficiencies in normal DNA repair capacity. One such syndrome, caused by mutations in mismatch repair genes, is hereditary nonpolyposis colorectal cancer. Endometrial cancer is a common phenotype of this familial syndrome, directly implicating DNA repair capacity in the pathogenesis of this disease. To date, the role of low-penetrant alleles in genes involved in mismatch repair or other DNA damage repair or response pathways has not been thoroughly studied in relation to endometrial cancer risk. This current project builds on existing resources to study efficiently and comprehensively, the importance of common genetic variation in 61 candidate genes in DNA repair-related pathways on endometrial cancer risk. Over the past year we have constructed an optimal array of "tagging" SNPs designed using Illumina genotyping technology that provide high predictability of common genetic variation in these candidate genes across multiple racial-ethnic populations. In this application, we will utilize prospectively collected biospecimens, risk factor and outcome data from two established endometrial cancer case-control studies nested within the Multiethnic Cohort study (cases, n = 542; controls, n = 1,234) and the California Teachers Study (cases, n = 580; controls, n = 1,160) to assess associations between these selected tagging SNPs (approximately 1,200) and all known missense variants (approximately 300) in these genes in relation to endometrial cancer risk. This study will use novel high-throughput genotyping technology as well as rigorous statistical analytic methods to account for multiple hypothesis testing, and allows for replication and cross- validation of findings across these cohorts. The ability to accurately identify high-risk sub-groups may have profound implications on endometrial cancer prevention as well as advance research aimed at targeted drug development.