Identifying and validating novel susceptibility genes for breast cancer

鉴定和验证乳腺癌的新易感基因

基本信息

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
项目类别：
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

项目摘要

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，大约227,000例浸润性乳腺癌的新病例和2012年预测的40,000例乳腺癌死亡。乳腺癌具有强大的遗传性成分，约有15％至20％的病例显示出这种疾病的家族史。对乳腺癌的敏感性与高风险基因（例如BRCA1和BRCA2）的稀有种系变异性有关，几种中等风险（3至5倍）的易感基因，例如PALB2和CHEK2，以及许多与适度（<1.5倍）的常见遗传变异相关的疾病风险。目前，高危基因和中间风险基因用于乳腺癌易感性的临床基因测试以及对具有乳腺癌家族史的个体的临床管理。但是，已知的诱发变体占所有家族性乳腺癌病例的50％。因此，许多患有乳腺癌家族史的人无法从信息丰富的临床基因检测和增强癌症风险评估和管理中受益。尽管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，但这些附加因素不太可能解释所有缺少乳腺癌遗传力的TE。因此，我们假设大量无法解释的乳腺癌家族风险是由于罕见的遗传变异型中高风险。在此，我们建议使用基于综合序列的方法来识别和表征新型的乳腺癌易感基因。我们已经完成了来自200个高危乳腺癌家族的多个种系DNA样品的整个外显林DNA样品，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AIM 1中，我们将在一项针对4,000例家族性乳腺癌病例和4,000例未受影响的对照的病例对照研究中验证400个候选基因。在AIM 2中，我们将通过评估罕见的重复蛋白质编码变体与乳腺癌风险之间的关联来采取不同的方法来鉴定乳腺癌的危险因素。我们将对8,000例乳腺癌病例和8,000例未受影响的对照组进行大型病例对照研究，以验证候选人。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访问大量的，注释良好的患者资源，在这项研究中具有既定背景，正在利用广泛的初步数据，并且能够利用该发现以使乳腺癌患者受益。因此，他的团队有好处，可以说明乳腺癌的大部分“缺乏遗传力”。