# Defining signatures of epigenetic sensitization to lung cancer in a mouse model

> **NIH NIH R21** · YALE UNIVERSITY · 2024 · $234,730

## Abstract

PROJECT SUMMARY
Epigenetic perturbations in cancer are widely recognized but poorly understood. A detailed understanding of
how latent epigenetic information contributes to tumorigenesis would enable us to stratify risk among
vulnerable patients, classify tumors based on epigenetic state, and better target therapeutic approaches.
Animal models of early-onset epigenetic perturbation offer a unique opportunity to study the potential contribution
of epigenetic signatures to prediction of cancer risk, since epigenetic changes precede tumor initiation in these
models and can therefore be separated from secondary effects of tumorigenesis. In preliminary studies, we
found that epigenetic changes induced by loss of the epigenetic regulator KDM6A (UTX) in the paternal germ
line in mice result in elevated lung tumor burden in offspring even when the mutant Kdm6a allele itself is not
inherited, implying that these offspring carry silent epigenetic perturbations that predispose to cancer. These
mice are an excellent experimental model for defining signatures of epigenetic sensitization that predict cancer
risk. Our central hypothesis is that preexisting, detectable epigenetic perturbations in lung tissue interact
with genetic driver mutations to enhance lung tumorigenesis, and that the resulting tumors have a
distinct epigenetic and genetic signature. The objective of this study is to define a signature of these
preexisting epigenetic changes in the lung in a mouse model and determine if a memory of this signature can
be detected in lung tumors. Aim 1 will define the transcriptional and epigenetic phenotypes of normal lung tissue
in epigenetically sensitized mice. Aim 2 will evaluate the molecular phenotypes of epigenetically sensitized lung
tumors using both spontaneous tumors and tumors induced by activated KRAS. If both are successful, the results
of the two Aims will be compared to identify signatures of epigenetic sensitization that are present in histologically
normal tissue and that persist in tumors. We expect this work to reveal new markers for epigenetic risk of lung
tumorigenesis and define the molecular signatures associated with prior epigenetic sensitization in tumors.
Future work will determine the extent to which such signatures can be applied to human populations in the clinic.

## Key facts

- **NIH application ID:** 10862318
- **Project number:** 1R21CA288677-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Bluma J Lesch
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $234,730
- **Award type:** 1
- **Project period:** 2024-07-09 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862318

## Citation

> US National Institutes of Health, RePORTER application 10862318, Defining signatures of epigenetic sensitization to lung cancer in a mouse model (1R21CA288677-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10862318. Licensed CC0.

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