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

DNA修复基因遗传变异与相关性的综合分析

• 批准号: 7266340
• 负责人: Christopher Alan Haiman
• 金额: $ 7.91万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7266340
• 关键词: Accounting; African American; Age; Age at Menarche; Alleles; American Cancer Society; Breast; California; Candidate Disease Gene; Case Study; Cell division; Cohort Studies; Colorectal Cancer; Contraceptive Usage; DNA; DNA Damage; DNA Repair; DNA Repair Gene; DNA Repair Pathway; DNA biosynthesis; Data; Development; Diagnosis; Disease; Endometrial Carcinoma; Endometrium; Environmental Risk Factor; Epidemiologic Methods; Epidemiology; Estrogen Therapy; Estrogens; Etiology; Event; Exposure to; Face; Family history of; Female; Gene-Modified; Genes; Genetic; Genetic Variation; Genomics; Germ-Line Mutation; Hawaiian population; Hereditary Nonpolyposis Colorectal Neoplasms; Hormone replacement therapy; Human; Human Genome; Hyperplasia; Individual; Japanese American; Latino; Life Style; Link; Linkage Disequilibrium Mapping; Lung; Malignant Neoplasms; Menopause; Methods; Mismatch Repair; Mitosis; Mitotic; Mutagens; Mutation; Nested Case-Control Study; Obesity; Oral; Outcome; Pathogenesis; Pathway interactions; Penetrance; Phenotype; Population; Postmenopause; Predisposition; Process; Progestins; Range; Rate; Replication Error; Research; Research Proposals; Resources; Risk; Risk Factors; Role; Single Nucleotide Polymorphism; Smoke; Somatic Mutation; Source; Stress; Syndrome; Testing; Thinking; Validation; Variant; Woman; Work; base; cancer risk; cell growth; cohort; coping; design; disorder risk; drug development; endometrial cancer prevention; genetic analysis; genotyping technology; hormone therapy; malignant phenotype; neoplastic; novel; parity; prospective; racial and ethnic; response; steroid hormone; teacher; tool

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.

描述(由申请人提供)：过量暴露于内源性和外源性雌激素会增加子宫内膜的细胞分裂，这被认为会增加体细胞突变发生的速度，并在随后的有丝分裂中固定，并在癌症的发展中起到启动作用。多种高度保守的机制已经进化出来，以识别和应对来自内源和外源对DNA的持续侮辱，并保持基因组的完整性。许多人类癌症综合征是由DNA修复基因罕见的胚系突变引起的，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性综合征的常见表型，直接与DNA修复能力有关。到目前为止，参与错配修复或其他DNA损伤修复或反应途径的基因中低渗透等位基因的作用与子宫内膜癌风险的关系尚未得到彻底研究。这项当前的项目建立在现有资源的基础上，有效和全面地研究在DNA修复相关途径中61个候选基因中共同的基因变异对子宫内膜癌风险的重要性。在过去的一年里，我们构建了一个使用Illumina基因分型技术设计的最佳SNPs“标记”阵列，可以对这些候选基因在多个种族-民族群体中的共同遗传变异提供高度可预测性。在这项应用中，我们将利用从多种族队列研究(病例，n=542；对照，n=1,234)和加州教师研究(病例，n=580；对照，n=1,160)中嵌套的两个已建立的子宫内膜癌病例对照研究中前瞻性收集的生物样本、风险因素和结果数据来评估这些选定的标记SNPs(约1,200)和这些基因中所有已知的错义变异(约300个)与子宫内膜癌风险的关系。这项研究将使用新的高通量基因分型技术以及严格的统计分析方法来解释多重假设检验，并允许在这些队列中复制和交叉验证结果。准确识别高危亚组的能力可能会对子宫内膜癌的预防以及针对靶向药物开发的进一步研究产生深远的影响。