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：
10188458
负责人：
Fergus Joseph Couch
金额：
$ 47.65万
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10188458
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/antagonist 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 triple-negative invasive breast carcinoma tumor variant of unknown significance

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/antagonist 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 triple-negative invasive breast carcinoma tumor variant of unknown significance

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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.

项目摘要乳腺癌和卵巢癌是美国女性中最常见的两种癌症。约15％ 20％的病例表现出乳腺癌或卵巢癌的家族史，表明可遗传的成分强。癌症易感基因面板的临床种系基因测试现在被广泛用于识别有这些癌症风险的妇女。鉴定已建立倾向基因中的致病突变根据基因，可以改善卵巢癌或乳腺癌的风险管理。病人及其家人。例如，早期发现乳腺癌的MRI筛查是建议所有在高风险乳腺癌基因和中等风险中患有致病突变的人，以及 BRCA1和BRCA2突变载体的载体可以受益于预防性乳房切除术和/或卵形切除术以减少癌症风险。此外，卵巢癌患者有种系或体细胞 BRCA1和BRCA2突变可能会受益于用铂剂或PARP抑制剂的靶向疗法受益。这这些临床干预措施的功效表明了鉴定基因中的致病突变的希望这些癌症易感性。但是，面板测试结果的实用性受到限制，因为在几个面板基因中，与突变相关的乳腺癌和卵巢癌的风险水平尚未很清楚。重要的是，最近的研究表明，Rad51c和 RAD51D与卵巢癌的风险大大增加，以及中等和高风险三重阴性乳腺癌（TNBC）和RAD51D突变分别与中等风险有关整体乳腺癌。尽管这些基因在乳腺癌和卵巢癌的敏感性中具有重要作用，但关于如何使用测试结果以使生殖线致病的人的利益还有很多尚待了解具有不确定意义的突变或变异，或肿瘤中基因的体细胞失活。在这个我们建议定义RAD51C和RAD51D突变的贡献，以精密医学为导向的项目致卵巢癌和乳腺癌。在AIM 1中，我们建议定义卵巢癌和乳腺癌的风险高危家族和一般人群中遗传的RAD51C和RAD51D突变。在AIM 2中，我们建议全面表征RAD51C和影响癌症风险和对治疗剂的反应的RAD51D，导致临床分类许多具有不确定意义的变体的相关性（VUS）。在AIM 3中，我们建议评估临床前模型中的RAD51C和RAD51D缺乏肿瘤的靶向治疗。在结束时研究我们期望对RAD51C和RAD51D相关的癌症的易感性有所改善以及卵巢肿瘤缺乏RAD51C或RAD51D对特定治疗剂的反应性。