Elucidating Cancer Risk in BRCA2 and RAD51 Variants

阐明 BRCA2 和 RAD51 变异的癌症风险

• 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
• 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

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.

项目摘要 精准医学的新时代发现并根据基因发现采取行动，无意中创造了一个巨大的 当遇到不确定意义的变体（VUS）时，临床困境。确定为BRCA或 接受遗传咨询的RAD 51 VUS携带者经历了困惑，焦虑和潜在的 错误的治疗计划目前的估计表明，10-20%的BRCA测序结果是不准确的。 VUS仅在美国就代表了数千名患者。这些数字可能会随着精确度的提高而上升 医药和商业上可获得的基因检测服务正在迅速部署。BRCA2 和RAD 51蛋白在DNA双链断裂的同源性定向修复（HDR）中起核心作用 （争端解决机构）。在医学肿瘤学环境中仍然缺乏解读HDR VUS的功能性诊断工具。 这是一个关键问题，因为生殖系HDR突变使个体易患癌症的高风险，而体细胞突变使个体易患癌症的高风险。 肿瘤中发现的突变可以极大地影响治疗计划。例如，合成致死策略 目前在肿瘤学中使用PARP抑制剂来选择性靶向HDR缺陷型肿瘤。 因此，体细胞肿瘤VUS的正确解释可以指导治疗选择。功能测定， 确定VUS的病理结果，以提供有关癌症的临床指导 风险和治疗选择。我们的长期目标是使分子和机制清晰， HDR用来修复DNA断裂的操作途径。通过使用高度协同的生化和 通过遗传学方法，我们旨在阐明VUS如何影响BRCA 2和RAD 51功能。我们的核心假设 基于细胞和生物化学功能的方法将成功区分致病性和 无害的HDR VUS。在目标1中，我们将建立基于细胞的互补试验， 相关试剂可用于鉴定致病性BRCA 2和RAD 51变体。整合肿瘤源性 将体细胞变异体植入我们的细胞模型中，将使二线疗法或新疗法的体外测试成为可能。 这些化合物为可能从靶向药物中获益的患者的临床实践提供了信息。在目标2中，我们 将确定致病性变体如何改变BRCA 2和RAD 51的生化功能。结果将 用于进一步完善我们对病理性HDR变异的机制理解，以及生物化学如何影响人类的免疫功能。 缺陷会增加患癌症的风险。我们的方法是创新的，因为我们独特的技能， 开发强大的基于细胞的生化功能测定，以剖析HDR机制，重点是 BRCA 2和RAD 51。这项拟议中的研究意义重大，因为它将为提供 患者和医生提供关于风险降低步骤和分层的临床可操作信息， 靶向治疗，如PARP抑制剂。此外，对病理变异的研究将提供深入了解 当HDR功能受到损害时，进入出错的分子通路。