权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

项目总结