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

基本信息

批准号：
8689753
负责人：
JOHN L HOPPER
金额：
$ 69.46万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
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/8689753
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

项目摘要

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）：乳腺癌的已知遗传危险因素仅占该疾病的家族风险的约30％（所谓的“缺失遗传力”），共同变异（频率> 10％）通过全基因组关联研究（GWAS）揭示了这一百分比的三分之一。家族风险的很大一部分可能是由于较不常见（1-10％）或罕见（<1％）的变异所致；遗传变异的空间尚未与乳腺癌风险进行全面探索。在此应用中，我们建议进行大规模的合作努力，以发现高家族/遗传风险的女性乳腺癌的遗传预测因子。为此，我们组建了一个国际研究人员，具有乳腺癌研究经验，他们渴望并愿意从其既定研究中汇集资源，标本和数据，以寻找这种主要癌症的新颖且较少的风险变体。在AIM 1中，我们提议进行全基因组的关联研究（对于频率低至1％的频率低1.5或0.67或以下的相对风险的功率为80％）。在第1阶段，我们将基于具有强大的疾病家族史以及对欧洲血统的3,000例控制，将基因型为500万SNP，以增加家族/遗传风险的3,000例乳腺癌病例。在第2阶段，我们将使用另外17,000例乳腺癌病例和17,000个欧洲血统对照的500个最重要的关联进行跟进。在非洲裔美国人，拉丁裔和日本样本以及与乳腺癌肿瘤亚型的关系中，将检查经过新的经过验证的风险变体。这项研究的第二个目的是进行假设，该假设在高家族/遗传风险的女性中对雌激素受体正和雌激素受体阴性乳腺癌进行GWAS分析，以寻求针对这些肿瘤亚型的风险变异。我们还将估计所有已知的风险变异（AIM 3）所解释的家族聚集量（多基因方差；遗传力），包括在AIM 1中发现的那些，使用基于人群的案例家庭研究，其中包含有关家族史和乳腺癌家族登记局（BCFR）亲戚的详细信息的详细信息和DNA的详细信息。我们的目标是改善综合风险模型Boadicea，以根据其遗传，家族史和流行病学特征来估算女性乳腺癌的终生风险。我们预计这项工作将大大提高人们对乳腺癌病因的了解，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实用程序。