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Elucidating Cancer Risk in BRCA2 and RAD51 Variants

阐明 BRCA2 和 RAD51 变异的癌症风险

基本信息

批准号：
9895655
负责人：
Ryan Brown Jensen
金额：
$ 38.32万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9895655
关键词：
Adoption Anxiety BRCA2 Protein BRCA2 gene Benchmarking Biochemical Biochemical Genetics Biological Biological Assay Biomedical Research Cell Line Cell model Cells Clinic Clinical Communities Complement Confusion Coupled DNA DNA Double Strand Break DNA Repair Data Defect Development Diagnostic Future Genes Genetic Genetic Counseling Goals Health High-Risk Cancer Human Human Biology Human Genome Individual Knowledge Length Medical Oncology Mission Modeling Molecular Mutation Nature Oncology Outcome Pathogenicity Pathologic Pathway interactions Patients Physicians Play Positioning Attribute Process Proteins Public Health Publishing Rad51 recombinase Reaction Research Resected Risk Reduction Role Selection for Treatments Somatic Mutation Stratification Testing Therapeutic Translating Tumor Suppressor Proteins Tumor-Derived United States National Institutes of Health Variant Work base cancer diagnosis cancer risk cancer therapy clinical practice clinically actionable clinically relevant clinically significant comparative design experience gene repair genetic approach genetic testing genome sequencing homologous recombination improved in vitro testing inhibitor/antagonist innovation insight novel precision medicine repaired skills targeted agent targeted treatment testing services tool treatment planning tumor variant of unknown significance

项目摘要

PROJECT SUMMARY The new era of precision medicine to discover and act upon genetic findings has inadvertently created a huge clinical dilemma when a variant of uncertain significance (VUS) is encountered. Patients identified as BRCA or RAD51 VUS carriers undergoing genetic counseling experience confusion, anxiety, and the potential for misguided treatment plans. Current estimates indicate that between 10-20% of BRCA sequencing results are VUS representing thousands of patients in the U.S. alone. These numbers will likely escalate as precision medicine and commercially available genetic testing services are being deployed at a rapid pace. The BRCA2 and RAD51 proteins play central roles in the homology-directed repair (HDR) of DNA double-strand breaks (DSBs). Functional diagnostic tools to decipher HDR VUS are still lacking in the setting of medical oncology. This is a critical issue as germline HDR mutations predispose individuals to a high risk for cancer while somatic mutations identified in tumors can dramatically impact treatment plans. For example, synthetic lethal strategies employing PARP inhibitors are currently being exploited in oncology to selectively target HDR deficient tumors. Therefore, the correct interpretation of a somatic tumor VUS can guide therapy selection. Functional assays to determine the pathological outcome of VUS are urgently needed to provide clinical guidance regarding cancer risk and treatment options. Our long-term objective is to bring molecular and mechanistic clarity to the operative pathways that HDR utilizes to repair DNA breaks. By using a highly synergistic biochemical and genetic approach, we aim to elucidate how VUS impact BRCA2 and RAD51 functions. Our central hypothesis is that a cell-based and biochemical functional approach will successfully differentiate pathogenic from harmless HDR VUS. In aim 1, we will establish cell-based complementation assays from which clinically relevant agents can be used to identify pathogenic BRCA2 and RAD51 variants. Integrating tumor-derived somatic variants into our cell-based models will enable in vitro testing of second-line therapies or novel compounds informing clinical practice of patients who could derive benefit from targeted agents. In aim 2, we will determine how pathogenic variants alter the biochemical functions of BRCA2 and RAD51. Results will be used to further refine our mechanistic understanding of pathological HDR variants and how biochemical defects translate into increased cancer risk. Our approach is innovative because of our unique skill set and development of robust cell-based and biochemical functional assays to dissect HDR mechanisms focused on BRCA2 and RAD51. The proposed research is significant because it will lay the groundwork to provide patients and physicians with clinically actionable information regarding risk reduction steps and stratification for targeted therapies such as PARP inhibitors. Furthermore, studies of pathological variants will provide insight into the molecular pathways that go awry when HDR functions are compromised.

项目总结