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性风险的约30%（所谓的“缺失遗传性”），通过全基因组关联研究（GWAS）发现的常见变异（频率bb10 %）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变异不常见（1-10%）或罕见（<1%）；遗传变异与乳腺癌风险的关系有待全面探索。在这项应用中，我们建议进行大规模的合作，以发现具有高家族/遗传风险的女性乳腺癌的遗传预测因子。为此，我们组建了一个具有乳腺癌研究经验的国际研究团队，他们渴望并愿意从已有的研究中汇集资源、标本和数据，以寻找这种主要癌症的新颖和不常见的风险变异。在目标1中，我们建议进行一项强有力的全基因组关联研究（对于频率低至1%的变异，检测相对风险为1.5或更高或0.67或更低的概率为80%）。在第一阶段，我们将对3000例家族/遗传风险增加的乳腺癌病例进行500万个snp基因型，这些病例基于有强烈的乳腺癌家族史，并对3000例欧洲血统的对照进行基因型分析。在第二阶段，我们将使用另外17000例乳腺癌病例和17000例欧洲血统的对照来追踪500个最重要的关联。将在非裔美国人、拉丁裔和日本样本中检查新的验证风险变异，以及与乳腺癌肿瘤亚型的关系。本研究的第二个目的是对具有高家族/遗传风险的女性雌激素受体阳性和雌激素受体阴性乳腺癌进行假设生成GWAS分析，以寻找这些肿瘤亚型特有的风险变异。我们还将使用基于人群的病例家庭研究，利用乳腺癌家庭登记（BCFR）中有关家族史和亲属dna的详细信息，估计由所有已知风险变异（目标3）解释的家族聚集（多基因方差；遗传性）的数量，包括在目标1中发现的那些变异。我们的目标是改进综合风险模型BOADICEA，根据女性的遗传、家族史和流行病学概况来估计女性一生患乳腺癌的风险。我们期望这项工作能够显著推进对乳腺癌病因学的认识，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效用。

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.