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

项目摘要/摘要 在BRCA1突变携带者中，乳腺癌的外显率似乎有很大的差异。累积风险 BRCA1突变携带者在70岁前患乳腺癌的风险估计在44%到80%之间。 BRCA1相关携带者的乳腺癌外显率和发病年龄存在差异 已观察到有害突变和基于人群的乳腺癌风险差异 还检测到具有相同突变的家庭和以诊所为基础的高危家庭。这些和其他 观察结果有力地表明，存在着改变癌症风险的常见基因变异 BRCA1突变携带者。我们在这项研究中的目标是确定BRCA1中乳腺癌风险的遗传修饰因素 携带者通过全基因组关联研究，目的是大幅提高对 这些肿瘤的病因以及与病理相关的三阴性乳腺肿瘤。这些修饰语 事实证明，这对改进BRCA1突变携带者的风险评估也很有用。我们计划实现以下目标 这是通过使用来自BRCA1突变携带者的DNA样本的多阶段方法来实现的 通过一个国际财团收集的。在第一阶段，我们的目标是将1500名BRCA1携带者与年轻患者进行基因分型 在550,000个常见变异上发现乳腺癌和1,500名未受影响的老年BRCA1携带者 与乳腺癌风险相关的变异。在第二阶段，我们将对13,180个变种进行最重要的评估 在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相关，并将数据与 第一阶段，增加统计力量。在第三阶段，将对384个最重要的变体进行进一步评估 2,000名受影响的BRCA1携带者和2,000名未受影响的BRCA1携带者，数据将与第一阶段的数据合并 2.同时，由于大多数BRCA1突变肿瘤是三阴性肿瘤，我们将评估 使用1,500个基础乳房的3期变异体与三阴性乳腺癌风险的关系 癌症患者和由乳腺癌协会联合会提供的1500名匹配对照。在舞台上 4将对包含最显著相关变异的基因组区域进行精细测绘 目的：确定BRCA1携带者乳腺癌风险改变的可能原因。项目叙事 BRCA1携带者乳腺癌风险基因修饰物的识别将有助于理解 BRCA1突变型乳腺癌和三阴性乳腺癌的病因学研究及开发新途径 治疗靶点。修改剂还可能导致改进的风险评估模型的开发，该模型 更好地区分高风险和低风险BRCA1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.