A genome-wide association study for breast cancer in BRCA1 mutation carriers

BRCA1 突变携带者乳腺癌的全基因组关联研究

• 批准号: 7533393
• 负责人: Fergus Joseph Couch
• 金额: $ 113.73万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-14 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7533393
• 关键词: Accounting; Affect; Age; Age of Onset; Ashkenazim; BRCA1 Mutation; BRCA1 gene; BRCA2 Mutation; Bilateral oophorectomy; Biological Assay; Breast; Cancer Patient; Categories; Caucasians; Caucasoid Race; Clinic; Clinical; Custom; DNA; DNA Resequencing; Data; Development; Diagnosis; Disease; Environmental Risk Factor; Etiology; Family; Future; Gene Expression; General Population; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genome; Genomics; Genotype; Germ-Line Mutation; Goals; Grouping; Individual; International; Lead; Malignant neoplasm of ovary; Mammary Neoplasms; Maps; Mastectomy; Mediating; Medicine; Meta-Analysis; Methods; Modeling; Modification; Mutation; Mutation Detection; Nonsense Mutation; Numbers; Ovariectomy; Pathway interactions; Patients; Penetrance; Population; Prevention approach; Preventive; Process; Prophylactic treatment; Public Health; Relative Risks; Risk; Risk Assessment; Risk Estimate; Role; Sampling; Single Nucleotide Polymorphism; Staging; Therapeutic; Tumor Suppressor Genes; Variant; Woman; Work; base; breast cancer diagnosis; cancer risk; cancer type; follower of religion Jewish; founder mutation; genetic risk factor; genetic variant; genome wide association study; improved; indexing; insight; mRNA Decay; malignant breast neoplasm; mutant; mutation carrier; novel; novel therapeutics; proband; prophylactic; therapeutic target; time use; tumor; tumor progression

DESCRIPTION (provided by applicant): The penetrance of breast cancer in BRCA1 mutation carriers appears to vary considerably. The cumulative risk of breast cancer by age 70 for a BRCA1 mutation carrier has been estimated at anywhere from 44% to 80%. Variable penetrance and age of onset of breast cancer among related BRCA1 carriers sharing the same deleterious mutations has been observed and differences in breast cancer risk between population-based families and high-risk clinic-based families with the same mutations have also been detected. These and other observations strongly suggest the existence of common genetic variants that modify the risk of cancer in BRCA1 mutation carriers. Our goal in this study is to identify genetic modifiers of breast cancer risk in BRCA1 carriers through a genome wide association study with the intent of substantially improving understanding of the etiology of these tumors as well as pathologically related triple negative breast tumors. These modifiers should also prove useful for improved risk assessment of BRCA1 mutation carriers. We propose to accomplish this through a multi-stage approach using DNA samples from BRCA1 mutation carriers that have been collected through an international consortium. In stage 1 we aim to genotype 1,500 BRCA1 carriers with young onset breast cancer and 1,500 older unaffected BRCA1 carriers on 550,000 common variants and identify variants associated with risk of breast cancer. In stage 2 we will evaluate the 13,180 variants most significantly associated with breast cancer risk in 2,000 affected and 2,000 unaffected carriers and combine the data with stage 1 to increase statistical power. In stage 3 the 384 most significant variants will be further evaluated in 2,000 affected and 2,000 unaffected BRCA1 carriers and the data will be combined with data from stages 1 and 2. In parallel, because most BRCA1 mutant tumors are triple negative tumors, we will evaluate associations between the variants in stage 3 and risk of triple negative breast cancer using 1,500 basal breast cancer patients and 1,500 matching controls provided by the Breast Cancer Association Consortium. In stage 4 fine mapping of the genomic regions containing the most significantly associated variants will be conducted to identify the variants that likely account for the modification of breast cancer risk in BRCA1 carriers. PUBLIC HEALTH RELEVANCE: The identification of genetic modifiers of breast cancer risk in BRCA1 carriers will be useful for understanding the etiology of BRCA1 mutant breast cancer and triple negative breast cancer and for developing novel therapeutic targets. The modifiers may also lead to development of improved risk assessment models that better discriminate between high and lower risk BRCA1 mutation carriers.

描述(申请人提供)：乳腺癌在BRCA1突变携带者中的外显率似乎有很大的差异。BRCA1突变携带者到70岁时患乳腺癌的累积风险估计在44%到80%之间。在拥有相同有害突变的相关BRCA1携带者中，观察到乳腺癌的外显率和发病年龄不同，也检测到具有相同突变的基于人群的家庭和基于临床的高危家庭之间的乳腺癌风险差异。这些和其他观察结果强烈表明，BRCA1突变携带者中存在改变癌症风险的常见基因变异。我们在这项研究中的目标是通过全基因组关联研究来确定BRCA1携带者乳腺癌风险的遗传修饰因素，目的是大幅提高对这些肿瘤以及与病理相关的三阴性乳腺肿瘤的病因的理解。这些修饰物也应该被证明对改进BRCA1突变携带者的风险评估有用。我们建议通过一个国际联盟收集的BRCA1突变携带者的DNA样本，通过分阶段的方法来实现这一点。在第一阶段，我们的目标是对1,500名年轻发病的乳腺癌BRCA1携带者和1,500名年龄较大的未受影响的BRCA1携带者进行550,000种常见变异的基因分型，并确定与乳腺癌风险相关的变异。在第二阶段，我们将评估2,000名受影响的携带者和2,000名未受影响的携带者中与乳腺癌风险最显著相关的13,180个变异，并将数据与第一阶段结合起来，以增加统计能力。在第三阶段，将在2,000名受影响的BRCA1携带者和2,000名未受影响的BRCA1携带者中进一步评估384个最重要的变异，并将数据与第一和第二阶段的数据结合起来。同时，由于大多数BRCA1突变肿瘤是三重阴性肿瘤，我们将使用1,500名基础乳腺癌患者和1,500名由乳腺癌协会提供的匹配对照来评估第三阶段的变异与三负乳腺癌风险之间的关系。在第四阶段，将对包含最显着相关变异的基因组区域进行精细作图，以确定可能导致BRCA1携带者乳腺癌风险改变的变异。公共卫生相关性：在BRCA1携带者中识别乳腺癌风险的基因修饰物将有助于了解BRCA1突变乳腺癌和三阴性乳腺癌的病因，并有助于开发新的治疗靶点。这些修饰物还可能导致改进的风险评估模型的开发，以更好地区分高风险和低风险的BRCA1突变携带者。