Consortium Study to Identify Breast Cancer Susceptibility Loci

描述(申请人提供)：乳腺癌是美国和世界其他许多地区女性最常见的恶性肿瘤。遗传因素在乳腺癌的病因中起着重要作用。最近的全基因组关联研究已经确定了乳腺癌的多个遗传易感基因。然而，这些新发现的遗传因素，以及以前报道的高外显性易感基因(如BRCA1和BRCA2基因)，只能解释乳腺癌遗传变异的一小部分。在这项申请中，我们提出了两个新的项目，这将显著提高我们对乳腺癌的遗传基础和用于遗传流行病学研究的方法的理解。第一个项目是以新成立的亚洲乳腺癌联合会为基础的全球乳腺癌研究，将包括从生活在世界各地的亚洲妇女中进行的11项研究中招募的27,000多名病例和对照。通过分析来自3,500个病例和3,500个对照的GWA扫描数据，我们将在独立的3,500个病例和3,500个对照中识别和评估前8,500个SNP，然后在6,700个病例和6,700个对照中验证大约100个SNP。在第二个项目中，我们将对3,000个病例和3,000个对照中的8个GWAS图谱区域进行测序，目标是识别这些区域乳腺癌的其他遗传风险变异，特别是低频变异。我们将选择最多180个有希望的SNP在2500个病例和2500个对照的独立集合中进行复制，然后选择前30个SNP在另一个2500个病例和2500个对照的独立集合中进行进一步评估。这是唯一在亚洲女性中进行的功能强大的GWA，因此也是现有的唯一能够发现乳腺癌基因变异的GWA，而这些变异在其他GWA中不太可能或更难识别。建议的测序项目代表了未来遗传关联研究的新模式。这两个新提出的项目将建立在几项进行得很好的、由NCI资助的研究的基础上，以产生大量的新信息，这些信息不仅有助于了解乳腺癌的生物学和遗传学，而且还有助于改进风险评估模型，并确定高风险妇女，以便以成本效益的方式预防乳腺癌。

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.