Identifying and validating novel susceptibility genes for breast cancer

鉴定和验证乳腺癌的新易感基因

• 批准号: 8694379
• 负责人: Fergus Joseph Couch
• 金额: $ 70.49万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-10 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8694379
• 关键词: Accounting; Affect; BRCA1 gene; BRCA2 gene; Base Sequence; Breast Cancer Risk Factor; CHEK2 gene; Cancer Patient; Cancer-Predisposing Gene; Candidate Disease Gene; Case-Control Studies; Cessation of life; Clinical; Clinical Management; Code; DNA; DNA Repair; Data; Disease; Exhibits; Family; Family history of; Family member; Frequencies; Gene Frequency; Genes; Genetic screening method; Genotype; Germ-Line Mutation; Goals; Hereditary Breast Carcinoma; Heritability; Individual; Lead; Malignant Neoplasms; Minor; Missense Mutation; Mus; Mutation; Patients; Penetrance; Population; Positioning Attribute; Predisposition; Prevention; Prevention strategy; Probability; Proteins; RNA Splicing; Recurrence; Relative (related person); Research; Resources; Risk; Risk Assessment; Risk Management; Sampling; Signal Transduction; Susceptibility Gene; Testing; Therapeutic; Validation; Variant; base; breast cancer family; cancer risk; design; disorder risk; embryonic stem cell; exome; exome sequencing; gene function; genetic variant; genome wide association study; high risk; improved; malignant breast neoplasm; member; non-genetic; novel; protein function; public health relevance; rare variant; risk variant; segregation; validation studies

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.

描述（由申请人提供）：乳腺癌是美国最常见的癌症之一，预计 2012 年将有约 227,000 例新发浸润性乳腺癌病例和 40,000 例乳腺癌死亡病例。乳腺癌具有很强的遗传性，大约 15% 至 20% 的病例有家族史。乳腺癌易感性与高风险基因（如 BRCA1 和 BRCA2）中的罕见种系变异、一些中风险（3 至 5 倍）易感基因（如 PALB2 和 CHEK2）以及许多与适度（<1.5 倍）增加的疾病风险相关的常见遗传变异有关。目前，高危基因和中危基因用于乳腺癌易感性的临床基因检测以及对有乳腺癌家族史的个体的临床管理。然而，已知的诱发变异仅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个体无法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受益。尽管非遗传因素和其他常见遗传变异也可能影响乳腺癌风险，但这些其他因素不太可能解释所有缺失的乳腺癌遗传性。因此，我们假设大量无法解释的乳腺癌家族风险是由于与以下疾病相关的罕见遗传变异造成的： 中到高风险。在此，我们建议使用基于序列的综合方法来识别和表征新型乳腺癌易感基因。我们已经完成了对来自 200 个高风险乳腺癌家族的多个种系 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 例未受影响的对照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反复出现的蛋白质编码变异与乳腺癌风险之间的关联，采用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药物。最后，在目标 3 中，我们将对目标 1 和 2 中的候选基因和变异进行功能研究，以改进对验证研究的致病性和非致病性变异的预测，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、注释清楚的患者资源，在本研究中拥有既定的背景，正在利用广泛的初步数据，并且有能力利用这些研究结果造福乳腺癌患者。因此，他的团队完全有能力解释乳腺癌“缺失的遗传性”的大部分原因。