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

高危女性乳腺癌的全基因组关联研究

• 批准号: 8515365
• 负责人: JOHN L HOPPER
• 金额: $ 66.81万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8515365
• 关键词: Accounting; African American; Alleles; BRCA1 gene; BRCA2 gene; Biological; Biology; Blood; Breast Cancer Genetics; Clinical; Collection; Complex; Data; Development; Disease; Early Diagnosis; Epidemiology; Estrogen receptor negative; Estrogen receptor positive; Etiology; European; Family; Family Cancer History; Family Study; Family history of; Frequencies; Future; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Risk; Genetic Variation; Genome; Genotype; Goals; Heritability; Heterogeneity; High Risk Woman; Human Genome; International; Japanese Population; Knowledge; Latino; Malignant Neoplasms; Malignant neoplasm of prostate; Measurement; Measures; Modeling; Mutation; Odds Ratio; Pathway interactions; Phase; Phenotype; Population; Predisposition; Prevention strategy; Preventive; Public Health; Recording of previous events; Relative (related person); Relative Risks; Research Design; Research Personnel; Resources; Risk; Risk Factors; Role; Sampling; Single Nucleotide Polymorphism; Specimen; Staging; Therapeutic; Tumor Subtype; Variant; Woman; Work; anticancer research; base; breast cancer family registry; cancer genome; cancer risk; cohort; design; disorder risk; experience; family genetics; follow-up; genetic pedigree; genetic risk factor; genetic variant; genome wide association study; high risk; improved; lifetime risk; malignant breast neoplasm; next generation; non-genetic; novel; population based; prognostic; public health relevance; public health research; risk variant; screening

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.

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的约 30%（所谓的“缺失遗传性”），通过全基因组关联研究 (GWAS) 揭示的常见变异（频率 >10%）解释了这一百分比的三分之一。很大一部分家族风险可能是由于不太常见（1-10%）或罕见（<1%）的变异引起的；尚未全面探索与乳腺癌风险关系的遗传变异空间。在本申请中，我们建议开展大规模合作，以发现具有高家族/遗传风险的女性患乳腺癌的遗传预测因素。为了这项工作，我们组建了一支由具有乳腺癌研究经验的国际研究人员组成的团队，他们渴望并愿意从已建立的研究中汇集资源、标本和数据，以寻找这种主要癌症的新颖且不太常见的风险变异。在目标 1 中，我们建议开展一项功效良好的全基因组关联研究（对于频率低至 1% 的变异，以 80% 的功效检测到 1.5 或更高或 0.67 或更低的相对风险）。在第一阶段，我们将对 3,000 例家族/遗传风险增加的乳腺癌病例（基于强大的疾病家族史）和 3,000 例欧洲血统对照进行 500 万个 SNP 的基因分型。在第二阶段，我们将使用另外 17,000 个乳腺癌病例和 17,000 个欧洲血统对照来追踪 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经过验证的风险变异，以及与乳腺癌肿瘤亚型的关系。这项研究的第二个目的是对具有高家族/遗传风险的女性中的雌激素受体阳性和雌激素受体阴性乳腺癌进行假设，进行 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族研究以及来自乳腺癌家族登记处 (BCFR) 的家族史和亲属 DNA 的详细信息，估计所有已知风险变异（目标 3）（包括目标 1 中发现的风险变异）所解释的家族聚集量（多基因变异；遗传力）。我们的目标是改进综合风险模型 BOADICEA，根据女性的遗传、家族史和流行病学特征来估计女性终生患乳腺癌的风险。我们期望这项工作能够显着增进对乳腺癌病因学的了解，并指导未来预防、早期检测、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用途。