# Genetic Loss-of-Function Studies of SETD2 in Kidney Tumorigenesis

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $542,407

## Abstract

Recent large-scale cancer genome sequencing studies have uncovered epigenetic regulators as a new major
class of cancer genes. SETD2 is one such example. SETD2 encodes a non-redundant H3K36
trimethyltransferase and is frequently mutated in a wide variety of human cancers. Based on TCGA datasets,
SETD2 is mutated in 13% of clear cell renal cell carcinoma (ccRCC), 8.9% of uterine corpus endometrial
carcinoma, 8.7% of lung adenocarcinoma, 6.9% of bladder urothelial carcinoma, 5.5% of stomach
adenocarcinoma, 5.4% of colorectal adenocarcinoma, 5.2% of melanoma, 4.6 % of hepatocellular carcinoma,
etc. The majority of SETD2 mutations identified in ccRCC and lung adenocarcinoma are truncating mutations
located upstream of the SRI domain that mediates the interaction of SETD2 with RNA polymerase II. Notably,
chromosome 3p where SETD2 resides is commonly deleted in both ccRCC and lung adenocarcinoma.
Altogether, these cancer genomics data strongly support a tumor suppressor role of SETD2. However, the
tumor suppressor function of SETD2 has not been fully established and how SETD2 loss-of-function promotes
tumorigenesis remains unclear. Herein, we have generated conditional Setd2 knockout mice to address the
tumor suppressor function/mechanisms of SETD2 in kidney cancer. Notably, SETD2 mutations often co-occur
with other well-established driver mutations, such as VHL and PBRM1 in ccRCC, MLL-fusions in acute
leukemia, and mutations activating the RTK/RAS/RAF pathway in lung adenocarcinomas, suggesting that
SETD2 loss probably cooperates with these driver mutations to promote tumorigenesis. Among cancers in
which SETD2 mutations have been reported, ccRCC shows the highest mutation rate. Although ccRCC has
long been recognized as a VHL loss-driven disease in which VHL is mutated or silenced in up to 80-90% of
ccRCC, deletion of Vhl alone is insufficient to induce kidney cancer in mice, indicating that additional genetic
event(s) is required to cooperate with VHL loss for kidney tumorigenesis. Here, we hypothesize that VHL loss
and SETD2 loss will cooperate to promote ccRCC development, which will be interrogated using genetically
engineered mouse models. Furthermore, our genomic studies indicate that SETD2 mutations are associated
with ccRCC progression and metastasis. We plan to establish patient-derived preclinical models of metastatic
SETD2 mutant ccRCC to investigate the role of SETD2 loss in promoting tumor metastasis. Our goals are to
establish physiological preclinical models of ccRCC based on human cancer genomics, to provide mechanistic
understanding of how dysregulated epigenetics conferred by SETD2 loss promotes tumor initiation and
metastasis, and to discover novel therapeutic vulnerabilities associated with loss of SETD2.

## Key facts

- **NIH application ID:** 10142379
- **Project number:** 5R01CA223231-04
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** EMILY H CHENG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $542,407
- **Award type:** 5
- **Project period:** 2018-05-07 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10142379

## Citation

> US National Institutes of Health, RePORTER application 10142379, Genetic Loss-of-Function Studies of SETD2 in Kidney Tumorigenesis (5R01CA223231-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10142379. Licensed CC0.

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