Investigating the Role of KEAP1 Germline and Somatic Mutations in Renal Cell Carcinoma

研究 KEAP1 种系和体细胞突变在肾细胞癌中的作用

• 批准号: 10740481
• 负责人: Maria Carlo
• 金额: $ 25.9万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740481
• 关键词: Address; Advisory Committees; Affect; Aggressive Clinical Course; Alleles; Antioxidants; Appointment; Award; Bioinformatics; Biological Models; Cancer Model; Cancer-Predisposing Gene; Cell Line; Clear cell renal cell carcinoma; Clinical; Collaborations; Core Facility; Cysteine; Development; Development Plans; Drug Targeting; Early identification; Ensure; Family; Fumarate Hydratase; Fumarate Hydratase Deficiency; Fumarates; Funding; Future; Gene Expression Profiling; Genes; Genetic; Genetic Predisposition to Disease; Genetic Services; Genitourinary system; Genomics; Germ-Line Mutation; Glutathione; Goals; Hereditary Renal Cell Carcinoma; Heritability; Histologic; Histology; Human Resources; Immunohistochemistry; In Vitro; Individual; Inherited; Institution; Laboratories; Lead; Loss of Heterozygosity; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mass Spectrum Analysis; Medical Genetics; Medicine; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Metabolic; Metabolic Pathway; Methodology; Molecular; Mutate; Mutation; Neurofibromin 2; Oncogenic; Oncology; Organoids; Pathologic; Pathway interactions; Patients; Phenotype; Positioning Attribute; Predisposition; Process; Prognosis; Renal Cell Carcinoma; Renal carcinoma; Research; Research Personnel; Resources; Risk; Risk Reduction; Role; Running; Scientist; Screening for cancer; Somatic Mutation; Susceptibility Gene; Syndrome; Techniques; Testing; Training; Translational Research; Tumor Suppressor Genes; United States; Up-Regulation; Variant; Work; cancer predisposition; cancer prevention; cancer therapy; career development; cell growth; cohort; experimental study; functional genomics; genetic epidemiology; genomic profiles; improved; in vivo; interest; loss of function; metabolomics; nephrogenesis; new therapeutic target; novel; patient derived xenograft model; patient subsets; predictive tools; response; screening; skills; targeted exome sequencing; targeted treatment; transcriptomics; translational model; tumor; tumorigenesis

PROJECT SUMMARY Candidate: Maria I. Carlo, MD is an Assistant Attending in Medicine at Memorial Sloan Kettering Cancer Center (MSK) with a dual appointment in the Genitourinary Oncology and Clinical Genetics services. Dr. Carlo's clinical and research interests are in hereditary RCC, a cancer that has a poor prognosis when identified in advanced stages. Under the mentorship of Kenneth Offit, MD, MPH and Ari Hakimi, MD she has begun work to elucidate the role of KEAP1 in the susceptibility to RCC and to define the phenotype of RCCs with KEAP1 mutations. Dr. Carlo's goal is to develop an independent laboratory to do translational work in the genetic predisposition to RCC and its implication for cancer screening and targeted treatment. Career Development Plan: Drs. Carlo, Offit, and Hakimi have developed a plan to ensure that Dr. Carlo has the necessary training, mentorship, and support to effectively transition to an independent researcher who can successfully lead genomic discovery studies in RCC. This plan entails formal courses in genetic epidemiology, bioinformatics, and cancer modeling, informal collaborations with scientists from MSK laboratories, and training with personnel from MSK core facilities. Dr. Carlo has organized an Advisory Committee with expertise relevant to her proposal, and they will guide her in successfully completing the goals of her proposed research. Dr. Offit and the Advisory Committee will also guide Dr. Carlo to ensure progress in the promotion process and garnering independent research funding towards the end of the K08 award period. Research Plan: Despite several known genetic RCC syndromes, the majority of familial RCC remains unexplained. The proposed project will use a large cohort of 928 patients with RCC who have undergone parallel tumor and germline targeted exome sequencing. In a subgroup of patients with RCC of unclassified histology, germline and somatic predicted loss-of-function variants were identified in KEAP1, which encodes a negative regulator of NRF2, the key activator of the antioxidant response pathway. These tumors are histologically similar to Fumarate Hydratase (FH)-deficient RCCs, which arise from germline mutations in the FH gene. Loss of function of FH or KEAP1 can activate the NRF2 pathway. Dr. Carlo hypothesizes that, similar to FH, KEAP1 loss-of-function germline variants increase risk of RCC, and mutations in KEAP1 contribute to the development of RCC in an NRF2-dependent manner. Dr. Carlo aims to (1) characterize KEAP1-mutated RCC using genomic, transcriptomic and metabolic techniques, and (2) delineate the effects of KEAP1 and FH mutations on malignant transformation in RCC model systems. The overarching goal is to elucidate the role and implications of germline and somatic KEAP1 mutations in RCC to direct cancer screening and develop rational targeted therapies.

项目摘要 候选人：马里兰州玛丽亚·卡洛（Maria I. 中心（MSK）在泌尿生殖器肿瘤学和临床遗传学服务中任命双重任命。博士 Carlo的临床和研究兴趣是遗传性RCC，这种癌症的预后不佳 在高级阶段确定。在医学博士Kenneth Offit的指导下，MPH和Ari Hakimi，医学博士 开始努力阐明KEAP1在RCC易感性中的作用并定义RCC的表型 与Keap1突变。卡洛博士的目标是开发一个独立的实验室，以在 遗传对RCC的易感性及其对癌症筛查和靶向治疗的影响。 职业发展计划：博士。 Carlo，Offit和Hakimi制定了一项计划，以确保Carlo博士拥有 必要的培训，指导和支持，以有效地过渡到可以 在RCC中成功铅基因组发现研究。该计划需要遗传流行病学的正式课程， 生物信息学和癌症建模，与MSK实验室科学家的非正式合作以及培训 来自MSK核心设施的人员。卡洛博士组织了一个具有专业知识的咨询委员会 与她的建议相关，他们将指导她成功完成她提议的研究的目标。 Offit博士和咨询委员会还将指导Carlo博士确保促销过程中的进步 在K08奖项期结束时获得独立的研究资金。 研究计划：尽管有几种已知的遗传RCC综合征，但大多数家族性RCC仍然存在 无法解释。拟议的项目将使用928例RCC患者的队列 平行肿瘤和种系具有外显子组测序。在一个未分类的RCC患者的亚组中 在KEAP1中鉴定了组织学，种系和躯体预测的功能丧失变体，该变体编码A NRF2的负调节剂，抗氧化剂响应途径的关键激活剂。这些肿瘤是 组织学上类似于富马酸水合物（FH）缺陷的RCC，这是由生殖线突变引起的 FH基因。 FH或KEAP1功能的损失可以激活NRF2途径。卡洛博士假设， 与FH相似，KEAP1功能丧失种系变体增加了RCC的风险，而KEAP1中的突变 以NRF2依赖性方式促进RCC的发展。卡洛博士的目标是（1） 使用基因组，转录组和代谢技术的KEAP1突变的RCC，（2）描绘 KEAP1和FH突变对RCC模型系统中恶性转化的影响。总体 目标是阐明种系和体细胞KEAP1突变在RCC中的作用和含义 筛查和开发有理目标疗法。