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

项目总结/摘要 BRCA 1突变携带者的乳腺癌发病率似乎差异很大。累积风险 据估计，BRCA 1突变携带者在70岁之前患乳腺癌的可能性在44%到80%之间。 BRCA 1相关携带者乳腺癌发病率和发病年龄的变化 已经观察到有害的突变，基于人群的乳腺癌风险差异 还发现了具有相同突变的家族和高风险临床家族。这些和其他 观察结果强烈表明，存在共同的遗传变异，改变癌症的风险， BRCA 1突变携带者。我们在这项研究中的目标是确定BRCA 1中乳腺癌风险的遗传修饰因子 通过全基因组关联研究， 这些肿瘤的病因以及病理相关的三阴性乳腺肿瘤。这些改性剂 这也将有助于改善BRCA 1突变携带者的风险评估。我们建议实现 这是通过一种多阶段的方法，使用来自BRCA 1突变携带者的DNA样本， 通过一个国际财团。在第一阶段，我们的目标是对1,500名BRCA 1携带者进行基因分型， 在550，000种常见变异中， 与乳腺癌风险相关的变异。在第二阶段，我们将评估13，180个最重要的变体 与2,000名受影响和2,000名未受影响的携带者的乳腺癌风险相关，并将数据联合收割机与 第一阶段，提高统计能力。在第3阶段，将进一步评估384个最重要的变体， 2,000名受影响和2,000名未受影响的BRCA 1携带者，数据将与第1阶段的数据相结合 和2.同时，由于大多数BRCA 1突变型肿瘤是三阴性肿瘤，我们将评估 使用1，500例基底乳腺癌患者，第3阶段变异与三阴性乳腺癌风险之间的相关性 癌症患者和1,500名匹配的对照，由乳腺癌协会联盟提供。在阶段 将对含有最显著相关变异的基因组区域进行4次精细作图 以确定可能导致BRCA 1携带者乳腺癌风险改变的变异。项目叙述 在BRCA 1携带者中识别乳腺癌风险的遗传修饰因子将有助于理解 BRCA 1突变型乳腺癌和三阴性乳腺癌病因学研究以及用于开发新的 治疗目标这些修改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。

PROJECT SUMMARY/ABSTRACT 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. PROJECT NARRATIVE 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.