Identifying and validating novel susceptibility genes for breast cancer

描述（由申请人提供）：乳腺癌是美国最常见的癌症之一，2012年预计约有227，000例新发浸润性乳腺癌病例和40，000例乳腺癌死亡。乳腺癌具有很强的遗传性，约15%至20%的病例表现出该疾病的家族史。乳腺癌易感性与高危基因（如BRCA 1和BRCA 2）中的罕见种系变异、几种中等风险（3至5倍）易感基因（如PALB 2和CHEK 2）以及许多与适度（<1.5倍）疾病风险增加相关的常见遗传变异相关。目前，高风险基因和中等风险基因用于乳腺癌易感性的临床基因检测和具有乳腺癌家族史的个体的临床管理。然而，已知的易感变异占所有家族性乳腺癌病例的不到50%。因此，许多有乳腺癌家族史的人不能从信息丰富的临床基因检测和增强的癌症风险评估和管理中获益。虽然非遗传因素和其他常见的遗传变异也可能影响乳腺癌的风险，但这些额外的因素不太可能解释乳腺癌的所有遗传性。因此，我们假设大量无法解释的乳腺癌家族风险是由于与乳腺癌相关的罕见遗传变异。 中度至高度风险。在此，我们建议使用全面的基于序列的方法来识别和表征新的乳腺癌易感基因。我们已经完成了来自200个高危乳腺癌家族的多个生殖系DNA样本的全外显子组测序，现在建议利用这些外显子组测序研究的结果来确定候选变异和基因对乳腺癌的贡献。在目标1中，我们将在4,000例家族性乳腺癌病例和4,000例未受影响对照的病例对照研究中验证400个候选基因。在目标2中，我们将通过评估罕见的复发性蛋白质编码变异与乳腺癌风险之间的关联，采取不同的方法来识别乳腺癌风险因素。我们将使用一项包含8,000例乳腺癌病例和8,000例匹配的未受影响对照的大型病例对照研究来验证候选人。最后，在目标3中，我们将对目标1和2的候选基因和变体进行功能研究，以改善验证研究中致病性和非致病性变体的预测，并了解与乳腺癌易感性相关的信号传导机制。参与该项目的研究团队可以获得大量注释良好的患者资源，在本研究中具有既定的背景，正在利用广泛的初步数据，并有能力利用这些发现为乳腺癌患者带来益处。因此，他的团队很好地解释了乳腺癌“缺失的遗传性”。

DESCRIPTION (provided by applicant): Breast cancer is one of the most common cancers in the US with approximately 227,000 new cases of invasive breast cancer and 40,000 breast cancer deaths predicted in 2012. Breast cancer has a strong heritable component with approximately 15% to 20% of cases exhibiting a family history of the disease. Susceptibility to breast cancer is associated with rare germline variants in high-risk genes such as BRCA1 and BRCA2, several intermediate-risk (3 to 5 fold) predisposition genes such as PALB2 and CHEK2, and many common genetic variants associated with modest (<1.5 fold) increased risk of disease. Currently, high-risk genes and intermediate risk genes are used for clinical genetic testing for breast cancer susceptibility and for clinical management of individuals with a family history of breast cancer. However, the known predisposing variants account for less than 50% of all familial breast cancer cases. Thus, many individuals with a family history of breast cancer cannot benefit from informative clinical genetic testing and enhanced cancer risk assessment and management. Although non-genetic factors and additional common genetic variants also may influence breast cancer risk, it is unlikely that these additional factors account for all of te missing heritability of breast cancer. Thus, we hypothesize that a significant amount of the unexplained familial risk of breast cancer is due to rare genetic variants that are associated with intermediate-to-high risk. Herein, we propose to identify and characterize novel breast cancer susceptibility genes using a comprehensive sequence-based approach. We have already completed whole exome sequencing of multiple germline DNA samples from 200 high-risk breast cancer families and now propose to leverage the results from these exome sequencing studies to establish the contribution of candidate variants and genes to breast cancer. In Aim 1, we will validate 400 candidate genes in a case-control study of 4,000 familial breast cancer cases and 4,000 unaffected controls. In Aim 2 we will take a different approach to the identification of breast cancer risk factors by evaluating associations between rare recurring protein-coding variants and breast cancer risk. We will use a large case-control study of 8,000 breast cancer cases and 8,000 matched unaffected controls to validate candidates. Finally, in Aim 3 we will conduct functional studies of the candidate genes and variants from Aims 1 and 2 in order to improve prediction of pathogenic and non-pathogenic variants for the validation studies and to understand the signaling mechanisms associated with predisposition to breast cancer. The research team involved in this project has access to large, well annotated patient resources, has an established background in this research, is leveraging extensive preliminary data, and has the ability to utilize the findings for the benefit of breast cancer patients. Thus, his team is well positioned to account for much of the "missing heritability" of breast cancer.