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

项目摘要 候选人：玛丽亚一世。Carlo，MD是Memorial Sloan Kettering Cancer的助理主治医师 中心（MSK）与生殖泌尿肿瘤和临床遗传学服务的双重任命。博士 Carlo的临床和研究兴趣是遗传性RCC，这是一种预后不良的癌症， 在高级阶段识别。在医学博士Kenneth Offit和医学博士Ari Hakimi的指导下，她拥有 开始研究KEAP 1在肾细胞癌易感性中的作用，并确定肾细胞癌的表型 KEAP1突变Carlo博士的目标是建立一个独立的实验室， RCC的遗传易感性及其对癌症筛查和靶向治疗的意义。 职业发展计划：Carlo博士、Offit博士和Hakimi博士制定了一个计划，以确保Carlo博士 必要的培训，指导和支持，以有效地过渡到一个独立的研究人员谁可以 成功领导RCC的基因组发现研究。该计划包括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 MSK核心设施的人员卡洛博士组织了一个咨询委员会， 他们将指导她成功地完成她提出的研究目标。 博士Offit和咨询委员会还将指导Carlo博士确保晋升过程的进展， 在K08奖励期结束时获得独立研究资金。 研究计划：尽管有几种已知的遗传性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名接受过肾癌治疗的RCC患者的大型队列。 平行肿瘤和生殖系靶向外显子组测序。在未分类的RCC患者亚组中， 在KEAP 1中鉴定了组织学、生殖系和体细胞预测的功能丧失变体，其编码一种 NRF2的负调节剂，抗氧化反应途径的关键激活剂。这些肿瘤 在组织学上类似于富马酸水合酶（FH）缺陷型RCC，其产生于 FH基因。FH或KEAP 1功能的丧失可以激活NRF 2通路。卡洛博士假设， 与FH相似，KEAP 1功能缺失种系变异增加RCC风险，KEAP 1突变 以NRF2依赖的方式促进RCC的发展。卡洛博士的目标是（1）描述 使用基因组学、转录组学和代谢技术，以及（2）描绘KEAP 1突变的RCC， KEAP 1和FH突变对RCC模型系统恶性转化的影响。总体 目的是阐明胚系和体细胞KEAP 1突变在肾细胞癌中的作用和意义 筛选和开发合理的靶向治疗。

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.