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: 8827527
• 负责人: Fergus Joseph Couch
• 金额: $ 140.82万
• 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/8827527
• 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; Hereditary Breast Carcinoma; Incidence; Individual; Inherited; Lead; Legal patent; Malignant Neoplasms; Medical; 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; proband; prophylactic; public health relevance; response; screening; segregation; sex; standard of care

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% 的病例有该疾病的家族史，表明具有很强的遗传因素。乳腺癌易感性与 BRCA1、BRCA2、PTEN、STK11、CDH1 和 TP53 的高外显率种系突变有关。此外，其他几个基因的遗传性失活突变也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。虽然 ATM 和 CHEK2 的失活突变与乳腺癌风险中度增加 3 至 7 倍相关，终生风险在 20% 至 50% 之间，但这些风险估计并不精确，而且人们对与其他易感基因失活突变相关的乳腺癌和其他癌症的风险知之甚少。现在可以对所有这些高风险和中风险易感基因进行临床基因检测。许多有乳腺癌、卵巢癌或其他癌症个人和家族史的女性正在寻求使用这些组合进行突变检测，由于“安吉丽娜的故事”，这种需求激增。初步数据表明，约 10% 的小组测试识别出截短突变 20% 产生意义不确定的变异 (VUS)，其形式为已知易感基因中未明确临床相关性的错义和内含子变化。尽管对于确定患者家族中乳腺癌的病因可能有用，但小组测试结果的临床解释仍然存在显着的局限性。特别是，与基因突变相关的乳腺癌和其他癌症的年龄相关风险在很大程度上尚不清楚。此外，尚未制定针对突变携带者的明确医疗管理建议。因此，这些测试的结果可能会导致混乱和不知情的医疗决策，从而导致重大伤害。我们建议在乳腺癌病例对照研究和高风险乳腺癌家族中对已知乳腺癌易感基因进行高通量突变筛查，以确定与这些基因有害突变相关的乳腺癌和其他癌症的风险，如下所示： 目标 1) 使用大型队列病例对照研究确定一般人群中与已知易感基因突变相关的乳腺癌风险；目标 2) 通过乳腺癌家族研究确定与基于组的易感基因失活突变相关的癌症的外显率；目标 3) 确定已知易感基因中 VUS 的临床相关性。在研究结束时，我们期望为普通人群和乳腺癌家族建立与基因有害突变相关的风险估计，从而大大改善对突变携带者的风险评估。此外，我们期望在已知易感基因中确定许多 VUS 的临床相关性。这项研究的结果还将提供必要的数据，为中度外显基因有害突变携带者建立护理医疗管理建议标准，这是一个未得到满足的关键需求。