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.