Consortium Study to Identify Breast Cancer Susceptibility Loci

确定乳腺癌易感性位点的联合研究

• 批准号: 8520969
• 负责人: Jirong Long
• 金额: $ 15.6万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-15 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8520969
• 关键词: ABCC1 gene; Accounting; African American; Architecture; Asia; Asian Americans; Asians; BRCA1 gene; BRCA2 gene; Breast Cancer Genetics; Breast Cancer Prevention; Cancer Biology; Chinese People; Complex; DNA; Data; Disease; Epidemiologic Studies; Ethnic group; Etiology; European; Evaluation; Frequencies; Funding; Future; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genomics; Goals; High Risk Woman; Human Genome; Japanese Population; Koreans; Life; Malignant Neoplasms; Maps; Methodology; Modeling; Parents; Pathway interactions; Penetrance; Persons; Phase; Play; Population; Predisposition; Primary Prevention; Recruitment Activity; Reporting; Research Design; Risk; Risk Assessment; Role; Sampling; Scanning; Secondary Prevention; Staging; Susceptibility Gene; Technology; United States; Variant; Woman; Women' s Health; base; cancer genetics; cancer genome; cancer risk; case control; cost; genetic association; genetic variant; genome wide association study; improved; malignant breast neoplasm; new technology; next generation; novel; public health relevance

DESCRIPTION (provided by applicant): Breast cancer is the most common malignancy among women in the United States and many other parts of the world. Genetic factors play an important role in the etiology of breast cancer. Recent genome-wide association studies (GWAS) have identified multiple genetic susceptibility loci for breast cancer. However, these newly- identified genetic factors, along with high-penetrance susceptibility genes reported previously (such as the BRCA1 and BRCA2 genes), explain only a small fraction of genetic variation for breast cancer. In this application, we propose two novel projects that will significantly advance our understanding of the genetic basis for breast cancer and the methodology used for genetic epidemiologic research. The first project is a GWAS based on the newly-established Asia Breast Cancer Consortium and will include over 27,000 cases and controls recruited from 11 studies conducted among Asian women living in various parts of the world. Through analyzing GWA scan data from 3,500 cases and 3,500 controls, we will identify and evaluate the top 8,500 SNPs in an independent set of 3,500 cases and 3,500 controls and then validate approximately the top 100 SNPs in 6,700 cases and 6,700 controls. In the second project, we will sequence eight GWAS-mapped regions in 3,000 cases and 3,000 controls with the goal of identifying additional genetic risk variants, particularly low- frequency variants, for breast cancer in these regions. We will select up to 180 promising SNPs for replication in an independent set of 2,500 cases and 2,500 controls and then select the top 30 SNPs for further evaluation in another independent set of 2,500 cases and 2,500 controls. This is the only well-powered GWAS conducted in Asian women, and thus is the only existing GWAS capable of discovering genetic variants for breast cancer that are unlikely or more difficult to identify in other GWAS. The proposed sequencing project represents a new model for future genetic association studies. These two newly-proposed projects will be built upon several well- conducted, NCI-funded studies to generate substantial novel information that will help to not only understand breast cancer biology and genetics, but also to improve risk assessment models and identify high-risk women for cost-efficient prevention of breast cancer. PUBLIC HEALTH RELEVANCE: Genetic factors play a major role in the etiology of breast cancers, yet only a small number of cases are explained by genetic factors identified thus far. The large epidemiologic study we propose will comprehensively evaluate genetic markers in relation to breast cancer risk. This study will generate valuable results for the identification of high-risk women for the primary and secondary prevention of breast cancer.

描述（由申请人提供）：乳腺癌是美国妇女和世界许多其他地区中最常见的恶性肿瘤。遗传因素在乳腺癌的病因中起重要作用。最近的全基因组关联研究（GWAS）已经确定了乳腺癌的多个遗传易感基因座。然而，这些新发现的遗传因素以及先前报道的高渗透易感基因（例如BRCA1和BRCA2基因）仅解释了乳腺癌遗传变异的一小部分。在此应用中，我们提出了两个新型项目，这些项目将大大提高我们对乳腺癌遗传基础的理解以及用于遗传流行病学研究的方法。第一个项目是基于新建立的亚洲乳腺癌财团的GWAS，其中包括27,000例病例和对照组中从世界各地的亚洲妇女进行的11项研究中招募的对照。通过分析来自3,500例病例和3,500个对照的GWA扫描数据，我们将在独立的3,500例病例和3,500个对照组中识别并评估前8500个SNP，然后在6,700例病例和6,700个对照中验证大约100个SNP。在第二个项目中，我们将在3,000例病例和3,000例控制中对八个GWAS映射区域进行测序，目的是确定这些区域中乳腺癌的其他遗传风险变异，尤其是低频变异。我们将在独立的2,500例病例和2,500个对照组中选择多达180个有希望的SNP进行复制，然后在另一组2500个案例和2,500个对照组中选择前30个SNP进行进一步评估。这是亚洲妇女中唯一能力的GWA，因此是唯一能够发现乳腺癌遗传变异的现有GWA，在其他GWAS中不太可能识别出乳腺癌的遗传变异。提出的测序项目代表了未来遗传关联研究的新模型。这两个新提出的项目将建立在几项经过良好的NCI资助的研究基础上，以产生大量的新型信息，这将有助于不仅了解乳腺癌的生物学和遗传学，还可以改善风险评估模型，并确定高危女性以预防乳腺癌。 公共卫生相关性：遗传因素在乳腺癌的病因中起着重要作用，但迄今为止发现的遗传因素仅解释了少数病例。我们提出的大型流行病学研究将全面评估与乳腺癌风险有关的遗传标记。这项研究将为鉴定高风险女性的初级和二级预防乳腺癌而产生宝贵的结果。