# Characterization of DNA repair in genomic and transcriptomic evolution of early lung carcinogenesis

> **NIH VA I01** · RLR VA MEDICAL CENTER · 2021 · —

## Abstract

Project Summary/Abstract
 Lung cancer remains the leading cause of cancer-related mortality in the United States and is particularly
problematic in U.S. veterans, who are at an increased risk for lung cancer resulting in approximately 5,500
excess veteran deaths per year. This is largely due to the late stage at which lung cancer is diagnosed. However,
resection of pre-malignant and stage I non-small cell lung cancers (NSCLC) results in cure in most patients.
Current recommendations include screening high-risk patients for lung cancer by low dose computed
tomography (CT) of the chest due to a 20% relative risk reduction in mortality. However, debate exists on the
patient population most likely to benefit from this intervention. Pre-malignant lesions such as atypical
adenomatous hyperplasia and early lung adenocarcinomas, identified as nodules on chest CT, are often
indistinguishable from benign nodules, which can lead to aggressive diagnostic and therapeutic interventions,
and possibly harm, in patients with benign nodules or delayed diagnosis in those with NSCLC. Better diagnostic
and therapeutic targets are needed to detect and treat pre-malignant and early non-small cell lung cancers when
cure is likely. A better understanding of the mechanisms underlying transition from pre-malignant to frankly
malignant non-small cell lung cancers is essential for more accurate and timely diagnosis and ultimately
improved survival.
 Genomic instability is a hallmark of cancer, and altered DNA repair pathways have been associated with
increased risk of lung cancers. The DNA repair protein, Xeroderma Pigmentosum Group C (XPC) gene
expression is decreased by chronic cigarette smoke in mice, and low XPC is identified early and often in human
lung adenocarcinomas. Our laboratory has discovered a critical role of XPC in protection against development
of cigarette smoke and carcinogen-induced lung adenocarcinoma development. We recently found that XPC
protects against histologic progression of mouse NTCU-induced lung squamous cell carcinomas. Our preliminary
data suggests progression of carcinogen-induced lung cancers in XPC deficient mice is associated with
increasing copy genomic complexity with higher histologic grade.
 Based on these findings, we hypothesize that decreased DNA repair by XPC leads to pre-malignant
lesions with characteristic mutational and epigenetic signatures that predict progression to lung cancer. We
propose to study this in three aims, using human samples of pre-malignant and early NSCLC specimens
complemented by our well-established, XPC-deficient urethane lung adenocarcinoma progression model. In Aim
1, we will identify the impact of XPC in transition from pre-malignant to early and late adenocarcinoma pathologic
grades by performing single cell sequencing on specimens isolated from urethane-treated XPC deficient mice,
and confirm orthologous changes in humans using archived genomic data (NCBI Gene Expression Omnibus)
and mechanistic in v...

## Key facts

- **NIH application ID:** 10257801
- **Project number:** 1I01BX005353-01A1
- **Recipient organization:** RLR VA MEDICAL CENTER
- **Principal Investigator:** Catherine Rufatto Sears
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10257801

## Citation

> US National Institutes of Health, RePORTER application 10257801, Characterization of DNA repair in genomic and transcriptomic evolution of early lung carcinogenesis (1I01BX005353-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10257801. Licensed CC0.

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