The contribution of RAD51C and RAD51D to breast and ovarian cancer

RAD51C 和 RAD51D 对乳腺癌和卵巢癌的贡献

基本信息

批准号：
10400738
负责人：
Fergus Joseph Couch
金额：
$ 45.14万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10400738
关键词：
Age BRCA1 Mutation BRCA1 gene BRCA2 Mutation BRCA2 gene Biochemical Breast Cancer Early Detection Breast Cancer Risk Factor Breast Cancer gene CRISPR/Cas technology Cancer Patient Case-Control Studies Cell Line Cells Cisplatin Classification Clinical Clinical Management Clinical Trials Cohort Studies Combined Modality Therapy Correlative Study DNA Repair Drug Targeting Exhibits Family Family history of Family member Gene Silencing General Population Genes Genetic study Genotype Germ-Line Mutation Guidelines Heritability Individual Inherited Lead Magnetic Resonance Imaging Malignant Neoplasms Malignant neoplasm of ovary Mammary Neoplasms Mastectomy Medical Genetics Mutation National Comprehensive Cancer Network Oncogenes Ovariectomy PARP inhibition Pathogenicity Patients Phenotype Platinum Compounds Population Study Pre-Clinical Model Predisposition Property Proteins RAD51C gene Resistance Risk Risk Assessment Risk Estimate Risk Management Role Signal Pathway Somatic Mutation Susceptibility Gene Test Result Testing Therapeutic Agents Treatment Efficacy Variant Woman cancer predisposition cancer risk cancer subtypes case control clinical care clinical development clinical efficacy clinically relevant defined contribution early screening effective therapy efficacy evaluation genetic testing high risk high risk population homologous recombination improved inhibitor inhibitor therapy insight lifetime risk malignant breast neoplasm mutation carrier novel novel therapeutic intervention ovarian neoplasm patient derived xenograft model population based precision medicine predicting response predictive marker prophylactic prophylactic mastectomy protein function recombinational repair response targeted treatment translational study treatment response triple-negative invasive breast carcinoma tumor variant of unknown significance

项目摘要

PROJECT SUMMARY Breast and ovarian cancer are two of the most common cancers among women in the US. Approximately 15% to 20% of cases exhibit a family history of breast or ovarian cancer suggesting strong heritable components. Clinical germline genetic testing of cancer predisposition gene panels is now widely used in an effort to identify women at risk for these cancers. The identification of pathogenic mutations in established predisposition genes can result in improved risk management for ovarian or breast cancer, depending on the gene, for tested patients and their family members. For instance, MRI screening for early detection of breast cancer is recommended for all individuals with pathogenic mutations in high and moderate risk breast cancer genes, and carriers of BRCA1 and BRCA2 mutation carriers can benefit from prophylactic mastectomy and/or oophorectomy for reduction of cancer risk. Furthermore, ovarian cancer patients with germline or somatic BRCA1 and BRCA2 mutations may benefit from targeted therapy with platinum agents or PARP inhibitors. The efficacy of these clinical interventions show the promise of identifying pathogenic mutations in genes that predispose to these cancers. However, the utility of results from panel testing has been limited because the levels of risk for breast and ovarian cancer associated with mutations in several of the panel genes has not been clear. Importantly, recent studies have established that germline pathogenic mutations in RAD51C and RAD51D are associated with substantially increased risks of ovarian cancer, and moderate and high risks of triple negative breast cancer (TNBC), respectively, and RAD51D mutations are associated with moderate risks of breast cancer overall. While these genes have important roles in susceptibility to breast and ovarian cancer, much remains to be learned about how to use testing results for the benefit of those with germline pathogenic mutations or variants of uncertain significance or with somatic inactivation of the genes in tumors. In this precision medicine oriented project we propose to define the contribution of RAD51C and RAD51D mutations to ovarian and breast cancer. In Aim 1 we propose to define the risks of ovarian and breast cancer associated with inherited RAD51C and RAD51D mutations in high-risk families and the general population. In Aim 2, we propose to comprehensively characterize the functional properties and functional domains of RAD51C and RAD51D that influence cancer risks and response to therapeutic agents, leading to classification of the clinical relevance of many variants of uncertain significance (VUS). In Aim 3, we propose to evaluate the influence of targeted therapy on RAD51C and RAD51D deficient tumors in preclinical models. At the conclusion of the study we expect to have improved understanding of RAD51C and RAD51D-associated cancer susceptibility and the responsiveness of ovarian tumors deficient in RAD51C or RAD51D to specific therapeutic agents.

项目概要乳腺癌和卵巢癌是美国女性最常见的两种癌症。约15% 20% 的病例有乳腺癌或卵巢癌家族史，表明具有很强的遗传成分。癌症易感基因组的临床种系基因检测现已广泛用于识别有患这些癌症风险的女性。鉴定已建立的易感基因中的致病突变根据测试的基因，可以改善卵巢癌或乳腺癌的风险管理患者及其家人。例如，用于早期发现乳腺癌的 MRI 筛查建议所有具有高风险和中风险乳腺癌基因致病性突变的个体，以及 BRCA1 和 BRCA2 突变携带者可以受益于预防性乳房切除术和/或卵巢切除术以降低癌症风险。此外，患有生殖细胞或体细胞的卵巢癌患者 BRCA1 和 BRCA2 突变可能受益于铂类药物或 PARP 抑制剂的靶向治疗。这这些临床干预措施的功效显示出识别基因致病突变的希望易患这些癌症。然而，面板测试结果的实用性受到限制，因为与某些基因组突变相关的乳腺癌和卵巢癌风险水平尚未发现已经清楚了。重要的是，最近的研究已经确定 RAD51C 和 RAD51C 的种系致病性突变 RAD51D 与卵巢癌风险显着增加以及中度和高度风险相关三阴性乳腺癌 (TNBC) 分别和 RAD51D 突变与中等风险相关乳腺癌的总体情况。虽然这些基因在乳腺癌和卵巢癌的易感性中发挥着重要作用，关于如何利用检测结果造福于生殖系致病菌的人，还有很多东西有待了解意义不确定的突变或变异或肿瘤中基因的体细胞失活。在这个我们建议以精准医学为导向的项目定义 RAD51C 和 RAD51D 突变的贡献卵巢癌和乳腺癌。在目标 1 中，我们建议定义与卵巢癌和乳腺癌相关的风险高危家庭和普通人群中存在遗传性 RAD51C 和 RAD51D 突变。在目标 2 中，我们提出全面表征 RAD51C 的功能特性和功能域 RAD51D 影响癌症风险和对治疗药物的反应，从而导致临床分类许多具有不确定意义的变体（VUS）的相关性。在目标 3 中，我们建议评估以下因素的影响：临床前模型中针对 RAD51C 和 RAD51D 缺陷肿瘤的靶向治疗。会议结束时我们希望这项研究能够加深对 RAD51C 和 RAD51D 相关癌症易感性的了解以及 RAD51C 或 RAD51D 缺陷的卵巢肿瘤对特定治疗药物的反应。