Genome-wide association study of breast cancer in high-risk women

描述(由申请人提供)：已知的乳腺癌遗传风险因素仅占该疾病家族风险(所谓的“缺失遗传性”)的约30%，而通过全基因组关联研究(GWAS)揭示的常见变异(频率和gt；10%)解释了这一百分比的三分之一。很大一部分家族性风险可能是由于不太常见(1-10%)或罕见(1%)的变异所致；这一遗传变异空间尚未全面探索与乳腺癌风险的关系。在这项应用中，我们建议开展一项大规模的合作努力，以揭示具有高家族/遗传风险的女性患乳腺癌的遗传预测因素。为此，我们组建了一支具有乳腺癌研究经验的国际研究团队，他们渴望并愿意从他们已有的研究中汇集资源、样本和数据，以寻找这种主要癌症的新的、不太常见的风险变量。在目标1中，我们建议进行一项强大的全基因组关联研究(使用80%的能力来检测频率低至1%的变异的相对风险为1.5或更高，或0.67或更低)。在第一阶段，我们将为3000名家族/遗传风险增加的乳腺癌病例和3000名欧洲血统的对照病例进行500万个SNPs的基因分型。在第二阶段，我们将使用另外的17,000例乳腺癌病例和17,000名欧洲血统的对照来跟踪500个最重要的关联。将在非洲裔美国人、拉丁美洲人和日本人的样本中检查新的有效风险变量，以及与乳腺癌肿瘤亚型的关系。这项研究的第二个目的将是对雌激素受体阳性和雌激素受体阴性的乳腺癌高家族/遗传风险女性进行一项假说生成分析，以寻找这些肿瘤亚型特有的风险变量。我们还将使用基于人群的病例家系研究来估计所有已知风险变量(AIM 3)所解释的家族聚集量(多基因变异；遗传力)，包括在AIM 1中发现的那些变量，该研究包含关于家族病史的详细信息和来自乳腺癌家族登记处(BCFR)亲属的DNA。我们的目标是改进全面的风险模型Boadicea，根据女性的基因、家族病史和流行病学特征来评估女性患乳腺癌的终生风险。我们希望这项工作将大大提高人们对乳腺癌病因的认识，并指导未来预防、早期发现、预后甚至治疗措施的发展，这些措施将具有广泛的临床和公共卫生实用价值。

DESCRIPTION (provided by applicant): Known genetic risk factors for breast cancer account for only ~30% of the familial risk of the disease (so-called 'missing heritability') with common variants (frequency >10%) revealed through genome-wide association studies (GWAS) explaining one-third of this percentage. A large fraction of familial risk is likely due to variants that are less common (1-10%) or rare (<1%); a space of genetic variation that has yet to comprehensively explored in relationship with breast cancer risk. In this application, we propose to undertake a large-scale collaborative effort to uncover genetic predictors of breast cancer in women at high familial/genetic risk. For this effort, we have assembled an international team of investigators with experience in breast cancer research who are eager and willing to pool resources, specimens and data from their established studies, to search for novel and less common risk variants for this major cancer. In Aim 1, we propose to conduct a well-powered genome-wide association study (with 80% power to detect a relative risk of 1.5 or more, or 0.67 or less, for a variant with frequency as low as 1%). In stage 1, we will genotype 5 million SNPs for 3,000 breast cancer cases at increased familial/genetic risk, based on having a strong family history of the disease, and 3,000 controls of European ancestry. In stage 2, we will follow-up the 500 most significant associations using an additional 17,000 breast cancer cases and 17,000 controls of European ancestry. Novel validated risk variants will be examined in African American, Latino and Japanese samples, as well as in relationship with breast cancer tumor subtypes. A second Aim of this study will be to conduct a hypothesis generating GWAS analysis of estrogen receptor positive and estrogen receptor negative breast cancer in women at high familial/genetic risk in search of risk variants that are specific for these tumor subtypes. We will also estimate the amount of familial aggregation (polygenic variance; heritability) explained by all known risk variants (Aim 3), including those discovered in Aim 1, using population-based case family studies with detailed information about family history and DNAs from relatives from the Breast Cancer Family Registry (BCFR). Our goal is to improve upon the comprehensive risk model BOADICEA for estimating a woman's lifetime risk of breast cancer based on her genetic, family history and epidemiologic profile. We expect this work to significantly advance knowledge of the etiology of breast cancer and to guide the development of future preventive, early detection, prognostic and even therapeutic measures that will have wide clinical and public health utility.