Resolving the cancer relevance of predisposition gene mutations

解决易感基因突变与癌症的相关性

• 批准号: 10053431
• 负责人: Fergus Joseph Couch
• 金额: $ 95.25万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10053431
• 关键词: ATM gene; Address; Adjuvant; African American; Age; Alleles; Award; BARD1 gene; BRCA1 Mutation; BRCA1 gene; BRCA2 Mutation; BRCA2 gene; Breast Cancer Patient; Breast Cancer Risk Factor; Breast Cancer therapy; CDH1 gene; CHEK2 gene; Clinical; Cohort Studies; Data; Decision Making; Disease; Estrogen receptor negative; Estrogen receptor positive; Exhibits; Family; Family history of; Gene Mutation; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Goals; Guidelines; Hereditary Malignant Neoplasm; Heritability; Individual; Inherited; Malignant Neoplasms; Mammary Neoplasms; Medical; Medical Genetics; Metastatic breast cancer; Minority; Modeling; Mutate; NF1 gene; Neoadjuvant Therapy; PTEN gene; Pathogenicity; Patients; Penetrance; Population; Predisposition; RAD51C gene; Risk; Risk Assessment; Risk Estimate; Risk Management; Series; Susceptibility Gene; TP53 gene; Test Result; Variant; Vision; cancer clinical trial; cancer risk; clinical application; clinically relevant; genetic panel test; genetic testing; genetic variant; improved; lifetime risk; malignant breast neoplasm; mutation carrier; novel; rare variant; response; risk variant; targeted treatment; therapy outcome; translational study; treatment response; triple-negative invasive breast carcinoma; variant of unknown significance

Breast cancer has a strong heritable component with approximately 15% of patients exhibiting a family history of the disease. My group recently established that inherited variants in 12 genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, and TP53) predispose to breast cancer (1, 2), that variants in all 12 genes increase risks of breast cancer in minority populations (3), and that variants in certain genes predispose only to estrogen receptor (ER) positive (ATM and CHEK2) or ER negative and triple negative breast cancer (TNBC) (BARD1, RAD51C and RAD51D) (4-6). Despite these major advances, clinical application of the information is still lacking. In addition, up to 50% of the familial risk of breast cancer remains unexplained. Under this award we plan to address clinically relevant issues, including improved application of genetic testing results for risk management of patients and improved selection of breast cancer therapy. In addition, we aim to identify new breast cancer predisposition genes that account for the missing heritability. The proposed studies are unified under a theme of advancing understanding of predisposition genetics. The studies are as follows: A. Age-specific and population-specific cancer risk assessment for predisposition gene variants. Results from hereditary multigene panel testing has limited clinical utility because only lifetime risk estimates of cancer by age 80 are available. Here we will estimate 5 and 10-year risks of breast cancer, so that patients can make decisions about medical management. In addition, we have evidence that specific genes have much higher penetrance in African Americans. We will determine the penetrance of predisposition gene variants using a large African American cohort study in order to modify risk management guidelines for this population. B. Functional characterization of predisposition gene variants. Variants of uncertain significance (VUS) identified by genetic testing remain a major problem for individuals receiving clinical genetic testing. We aim to combine high-throughput functional analysis of VUS in ATM, BRCA2 and PALB2 genes with genetic data from families in integrated models to determine the clinical relevance of many VUS alterations. C. Therapeutic response for breast cancer predisposition genes. The responsiveness of breast tumors associated with predisposition gene variants to standard or targeted therapy is only known for BRCA1 and BRCA2 mutation carriers. Here we aim to identify all patients with pathogenic variants in the commonly mutated BRCA1, BRCA2, PALB2, ATM and CHEK2 genes from a series of neo-adjuvant, adjuvant and metastatic breast cancer clinical trials and to assess response to therapy and outcome. D. Identification of novel breast cancer predisposition alleles. The common and rare risk alleles for breast cancer account for only 50% of the familial risk in the population. In an effort to identify the missing heritability we will collaborate with Regeneron Inc. through our SIMPLEXO consortium to identify common and rare alleles associated with breast cancer risk in 45,000 breast cancer patients.

乳腺癌具有很强的遗传性，大约 15% 的患者有家族史 的疾病。我的团队最近确定 12 个基因（ATM、BARD1、BRCA1、BRCA2、 CDH1、CHEK2、NF1、PALB2、PTEN、RAD51C、RAD51D 和 TP53) 易患乳腺癌 (1, 2)， 所有 12 个基因的变异都会增加少数群体患乳腺癌的风险 (3)，并且某些基因的变异 基因仅倾向于雌激素受体 (ER) 阳性（ATM 和 CHEK2）或 ER 阴性和三阴性 乳腺癌 (TNBC)（BARD1、RAD51C 和 RAD51D）(4-6)。尽管取得了这些重大进展，但临床应用 的信息仍然缺乏。此外，高达 50% 的乳腺癌家族风险仍无法解释。 根据该奖项，我们计划解决临床相关问题，包括改进基因检测的应用 患者风险管理和改进乳腺癌治疗选择的结果。此外，我们的目标是 确定新的乳腺癌易感基因，以解释缺失的遗传性。拟议的研究 统一在促进对易感遗传学的理解的主题下。研究结果如下： A. 针对易感基因变异的年龄特异性和人群特异性癌症风险评估。结果来自 遗传性多基因面板测试的临床实用性有限，因为只能根据年龄对癌症的终生风险进行评估 80 可用。在这里我们将估计5年和10年患乳腺癌的风险，以便患者做出决定 关于医疗管理。此外，我们有证据表明特定基因在 非裔美国人。我们将使用大型非洲样本来确定易感基因变异的外显率 美国队列研究旨在修改该人群的风险管理指南。 B.易感基因变异的功能特征。意义不确定的变体 (VUS) 对于接受临床基因检测的个人来说，通过基因检测发现的问题仍然是一个主要问题。我们的目标是 将 ATM、BRCA2 和 PALB2 基因中 VUS 的高通量功能分析与来自 家庭在综合模型中确定许多 VUS 改变的临床相关性。 C.乳腺癌易感基因的治疗反应。乳腺肿瘤的反应性 与标准或靶向治疗的易感基因变异相关的已知仅是 BRCA1 和 BRCA2突变携带者。在这里，我们的目标是识别常见突变中具有致病性变异的所有患者 来自一系列新辅助、辅助和转移性乳腺的 BRCA1、BRCA2、PALB2、ATM 和 CHEK2 基因 癌症临床试验并评估对治疗的反应和结果。 D. 新型乳腺癌易感等位基因的鉴定。乳房常见和罕见的风险等位基因 癌症仅占人口家族风险的 50%。努力确定缺失的遗传力 我们将通过 SIMPLEXO 联盟与 Regeneron Inc. 合作，识别常见和罕见的等位基因 与 45,000 名乳腺癌患者的乳腺癌风险相关。