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

> **NIH NIH K08** · SLOAN-KETTERING INST CAN RESEARCH · 2024 · $266,666

## Abstract

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.

## Key facts

- **NIH application ID:** 10875299
- **Project number:** 5K08CA272960-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Maria Carlo
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $266,666
- **Award type:** 5
- **Project period:** 2023-07-01 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10875299

## Citation

> US National Institutes of Health, RePORTER application 10875299, Investigating the Role of KEAP1 Germline and Somatic Mutations in Renal Cell Carcinoma (5K08CA272960-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10875299. Licensed CC0.

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