Resolving the cancer relevance of predisposition gene mutations

解决易感基因突变与癌症的相关性

基本信息

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
项目类别：
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

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

展开

项目摘要

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.

乳腺癌具有强大的可遗传成分，约有15％的患者表现出家族史疾病。我的小组最近确定了12个基因的遗传变体（ATM，BARD1，BRCA1，BRCA2， CDH1，CHEK2，NF1，PALB2，PTEN，RAD51C，RAD51D和TP53）倾向于乳腺癌（1，2）所有12种基因的变异都会增加少数族裔乳腺癌的风险（3），并且某些变异基因仅对雌激素受体（ER）阳性（ATM和CHEK2）或ER阴性和三重阴性易感性乳腺癌（TNBC）（Bard1，Rad51c和Rad51d）（4-6）。尽管有这些重大进展，但临床应用信息仍然缺乏。此外，多达50％的乳腺癌风险仍无法解释。根据该奖项，我们计划解决临床相关问题，包括改善基因测试的应用患者风险管理的结果以及改善乳腺癌治疗的选择。此外，我们的目标是确定解释缺失遗传力的新乳腺癌倾向基因。提出的研究以推进对倾向遗传学的理解为主题的统一。研究如下： A.易感基因变异的年龄特异性和人群特异性癌症风险评估。结果遗传性多基因面板测试的临床公用事业有限，因为只有年龄限制癌症的终生风险估计 80可用。在这里，我们将估计乳腺癌的5年和10年风险，以便患者可以做出决定关于医疗管理。此外，我们有证据表明特定基因的外渗性高得多非裔美国人。我们将使用大型非洲人确定倾向基因变体的渗透率美国队列研究是为了修改该人群的风险管理指南。 B.倾向基因变体的功能表征。不确定意义的变体（VUS）对于接受临床基因检测的个体而言，通过基因检测确定仍然是一个主要问题。我们的目标将ATM，BRCA2和PALB2基因VU的高通量功能分析与来自综合模型中的家庭，以确定许多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疗法的倾向基因变异相关，仅在BRCA1和 BRCA2突变载体。在这里，我们的目的是确定通常突变中患有致病性变异的所有患者 BRCA1，BRCA2，PALB2，ATM和CHEK2基因来自一系列新辅助，辅助和转移性乳房癌症临床试验并评估对治疗和结果的反应。 D.鉴定新型乳腺癌易感性等位基因。乳房的常见和稀有风险等位基因癌症仅占人群中家族风险的50％。为了确定缺失的遗传力我们将通过我们的纯正财团与Regeneron Inc.合作，以识别常见和稀有等位基因与45,000名乳腺癌患者的乳腺癌风险有关。