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

描述（由申请人提供）：BRCA 1突变携带者的乳腺癌发病率似乎差异很大。BRCA 1突变携带者到70岁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BRCA 1携带者中，观察到乳腺癌发病率和发病年龄的变化，并且还检测到具有相同突变的基于人群的家庭和基于高风险临床的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，存在改变BRCA 1突变携带者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全基因组关联研究来确定BRCA 1携带者中乳腺癌风险的遗传修饰因子，目的是实质性地提高对这些肿瘤以及病理相关的三阴性乳腺肿瘤的病因学的理解。这些修饰物也应该被证明对改善BRCA 1突变携带者的风险评估有用。我们建议通过一个多阶段的方法来实现这一目标，使用通过国际财团收集的BRCA 1突变携带者的DNA样本。在第一阶段，我们的目标是对1，500名年轻发病的乳腺癌BRCA 1携带者和1，500名老年未受影响的BRCA 1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种变异，并将数据与第一阶段联合收割机结合以增加统计功效。在第3阶段，将在2,000名受影响和2,000名未受影响的BRCA 1携带者中进一步评估384种最重要的变异，并将数据与第1阶段和第2阶段的数据相结合。同时，由于大多数BRCA 1突变肿瘤是三阴性肿瘤，我们将使用乳腺癌协会联盟提供的1，500名基底乳腺癌患者和1，500名匹配对照来评估3期变异与三阴性乳腺癌风险之间的关联。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定位，以识别可能导致BRCA 1携带者乳腺癌风险改变的变异。公共卫生相关性：在BRCA 1携带者中识别乳腺癌风险的遗传修饰物将有助于理解BRCA 1突变乳腺癌和三阴性乳腺癌的病因，并开发新的治疗靶点。这些修饰物也可能导致改进的风险评估模型的发展，更好地区分高风险和低风险BRCA 1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.