Risk and penetrance of mutations from breast cancer testing panels.

乳腺癌检测组突变的风险和外显率。

• 批准号: 9132729
• 负责人: Fergus Joseph Couch
• 金额: $ 129.99万
• 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: 2014-09-25 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9132729
• 关键词: Academic Medical Centers; Accounting; Address; Age; BARD1 gene; BRCA1 Mutation; BRCA1 gene; BRCA2 Mutation; BRCA2 gene; Base Ratios; Biological Assay; Birth; Breast; CDH1 gene; CHEK2 gene; Cancer-Predisposing Gene; Case-Control Studies; Cessation of life; Classification; Clinical; Clinical Management; Confusion; Data; Development; Diffuse; Disease; Etiology; Exhibits; Family; Family Study; Family history of; Gene Mutation; General Population; Genes; Genetic; Genetic screening method; Genotype; Germ-Line Mutation; Health; Hereditary Breast Carcinoma; Incidence; Individual; Inherited; Lead; Legal patent; Malignant Neoplasms; Medical; Medical Genetics; Mutation; Oncogenes; Operative Surgical Procedures; Ovarian; PTEN gene; Pathogenicity; Patients; Penetrance; Peutz-Jeghers Syndrome; Population; Predisposition; RAD51C gene; Recommendation; Research; Risk; Risk Assessment; Risk Estimate; Risk Management; STK11 gene; Susceptibility Gene; TP53 gene; Test Result; Testing; Therapeutic; Variant; Vendor; Woman; XRCC2 gene; age related; base; breast cancer family; cancer risk; clinically relevant; cohort; community setting; high risk; improved; lifetime risk; malignant breast neoplasm; malignant stomach neoplasm; mutation carrier; mutation screening; proband; prophylactic; response; screening; segregation; sex; standard of care; variant of unknown significance

DESCRIPTION (provided by applicant): Breast cancer is one of the most common cancers in the US. Approximately 15% to 20% of cases exhibit a family history of the disease suggesting a strong heritable component. Susceptibility to breast cancer is associated with high-penetrance germline mutations in BRCA1, BRCA2, PTEN, STK11, CDH1, and TP53. In addition, inherited inactivating mutations in several other genes have been associated with familial breast cancer. These include ATM, CHEK2, PALB2, BRIP1, BARD1, RAD51C, RAD51D, XRCC2, NBN, RAD50, and MRE11A. While inactivating mutations in ATM and CHEK2 have been associated with moderate 3 to 7-fold increased risk of breast cancer with lifetime risks of between 20% and 50%, these risk estimates are imprecise and little is known about the risk of breast and other cancers associated with inactivating mutations in the other predisposition genes. Clinical genetic testing for all of these high and moderate risk predisposition genes is now available. Many women, with personal and family history of breast, ovarian or other cancers, are pursuing testing for mutations with these panels, which has seen an upsurge in demand in response to 'Angelina's story'. Initial data suggest that ~10% of panel tests identify truncating mutations and 20% yield variants of uncertain significance (VUS) in the form of missense and intronic changes of undefined clinical relevance in the known predisposition genes. Although potentially useful for establishing the etiology of breast cancer in a patient's family, there remain significant limitatins in the clinical interpretation of the results from the panel testing. In particular, the age-relate risk of breast and other cancers associated with mutations in the genes are largely undefined. Furthermore, clear medical management recommendations for mutation carriers have not been developed. Thus, the results of these tests can lead to confusion and uninformed medical decisions that can result in significant harm. We propose to use high-throughput mutation screening of known breast cancer predisposition genes in breast cancer case-control studies and high-risk breast cancer families to establish the risks of breast and other cancers associated with deleterious mutations in these genes as follows: Aim 1) Establish the risk of breast cancer in the general population associated with mutations in known predisposition genes using large cohort-based case-control studies; Aim 2) Define the penetrance of cancers associated with inactivating mutations in panel-based predisposition genes through breast cancer family studies; Aim 3) Determine the clinical relevance of VUS in the known predisposition genes. At the conclusion of the study, we expect to establish risk estimates associated with deleterious mutations in the genes for the general population and breast cancer families, leading to much improved risk assessment for mutation carriers. In addition, we expect to establish the clinical relevance of many VUS in the known predisposition genes. The results of this study will also provide the necessary data to establish standard of care medical management recommendations for carriers of deleterious mutations in moderate penetrance genes, a critical unmet need.

描述（由申请人提供）：乳腺癌是美国最常见的癌症之一。大约15％至20％的病例表现出该疾病的家族史，表明具有强大的可遗传成分。乳腺癌的敏感性与BRCA1，BRCA2，PTEN，STK11，CDH1和TP53中的高渗透率种系突变有关。此外，其他几个基因的遗传失活突变与家族性乳腺癌有关。其中包括ATM，CHEK2，PALB2，BRIP1，BARD1，RAD51C，RAD51D，XRCC2，NBN，RAD50和MRE11A。尽管ATM和CHEK2中的灭活突变与中等3至7倍的乳腺癌风险增加有关，终生风险在20％至50％之间，但这些风险估计不准确，对其他乳腺癌和其他与其他倾向基因灭活突变相关的乳腺癌的风险知之甚少。所有这些高和中等风险易感基因的临床基因测试现已获得。许多具有乳房，卵巢或其他癌症的个人和家族史的妇女正在使用这些小组进行突变进行测试，这些小组对“ Angelina的故事”的需求激增。初始数据表明，约有10％的面板测试确定了截断突变和 在已知的倾向基因中未定义的临床相关性的错义和内含性变化的形式的不确定意义（VU）的屈服变异为20％。尽管对于在患者家庭中建立乳腺癌的病因可能有可能有用，但在临床解释小组测试结果中仍然存在明显的限制。特别是，与基因突变相关的乳腺癌和其他癌症的年龄风险在很大程度上不确定。此外，尚未开发有关突变载体的明确医疗管理建议。因此，这些测试的结果可能导致混乱和不知情的医疗决策，可能导致重大伤害。我们建议在乳腺癌病例对照研究和高危乳腺癌家族中使用已知乳腺癌易感基因的高通量突变筛查，以建立乳腺癌和其他与这些基因中有害突变相关的癌症的风险，如下所示：目标：1）使用大型病例研究中的一般人群中的乳腺癌风险相关的乳腺癌风险。目的2）通过乳腺癌家族研究来定义与基于面板的倾向基因失活突变相关的癌症的外观；目标3）确定VUS在已知倾向基因中的临床相关性。在研究结束时，我们期望建立与普通群体和乳腺癌家族基因中有害突变相关的风险估计，从而导致突变载体的风险评估大大改善。此外，我们期望在已知的倾向基因中建立许多VU的临床相关性。这项研究的结果还将提供必要的数据，以建立中等渗透基因中有害突变携带者的护理医疗管理建议，这是一个关键的未满足需求。