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

描述（由申请人提供）：BRCA1突变携带者的乳腺癌外显率似乎差异很大。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。在具有相同有害突变的相关BRCA1携带者中，观察到乳腺癌的不同外显率和发病年龄，并检测到具有相同突变的以人群为基础的家庭和以临床为基础的高风险家庭之间的乳腺癌风险差异。这些和其他观察结果有力地表明，在BRCA1突变携带者中存在改变癌症风险的常见遗传变异。我们在这项研究中的目标是通过一项全基因组关联研究，确定BRCA1携带者乳腺癌风险的遗传修饰因子，目的是大大提高对这些肿瘤以及病理相关的三阴性乳腺肿瘤病因的理解。这些修饰剂也被证明有助于改善BRCA1突变携带者的风险评估。我们建议通过多阶段的方法来实现这一目标，使用通过国际联盟收集的BRCA1突变携带者的DNA样本。在第一阶段，我们的目标是对1500名年轻发病乳腺癌的BRCA1携带者和1500名未受影响的老年BRCA1携带者进行55万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，我们将在2000名受影响和2000名未受影响的携带者中评估与乳腺癌风险最显著相关的13180种变异，并将数据与第一阶段相结合，以增加统计能力。在第三阶段，将在2000名受影响和2000名未受影响的BRCA1携带者中进一步评估384个最重要的变异，并将数据与第一阶段和第二阶段的数据结合起来。同时，由于大多数BRCA1突变肿瘤是三阴性肿瘤，我们将使用由乳腺癌协会协会提供的1500名基底乳腺癌患者和1500名匹配对照，评估3期变异与三阴性乳腺癌风险之间的关系。在第4阶段，将对包含最显著相关变异的基因组区域进行精细制图，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：确定BRCA1携带者乳腺癌风险的遗传修饰因子将有助于了解BRCA1突变型乳腺癌和三阴性乳腺癌的病因学，并有助于开发新的治疗靶点。这些修饰因子还可能导致改进的风险评估模型的发展，从而更好地区分高风险和低风险的BRCA1突变携带者。

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.