Research recently published in Oncotarget details how the combination of cigarette smoke exposure and a body’s diminished capacity to repair DNA causes extensive lung damage and a significantly increased risk of cancer. First author Nawar Al Nasrallah, MD, and corresponding author Catherine R. Sears, MD, led the study, “Cigarette Smoke and Decreased DNA Repair by Xeroderma Pigmentosum Group C Use a Double Hit Mechanism for Epithelial Cell Lung Carcinogenesis.”
The researchers examined the relationship between the genetic and environmental factors, specifically the role of xeroderma pigmentosum group C (XPC) — a critical nucleotide excision repair (NER) protein that recognizes and repairs DNA that have been damaged by tobacco smoke. They discovered that low levels of XPC, a common consequence for lung cancer patients, made it more difficult for lung cells to restore DNA and reduce harmful damage.
This causation, the researchers noted in a press release, makes cells unstable and more likely to develop lung cancer.
“Our study suggests that cigarette smoke exposure leads to decreased XPC mRNA expression, exacerbates total and oxidative DNA damage, hinders NER and may contribute to lung cancer development,” said Dr. Sears, who is a physician-scientist at the Indiana University Simon Cancer Center in Indianapolis and co-director of the pulmonary oncology clinic at the Richard L. Roudebush VA Medical Center.
The study’s findings demonstrate a double hit model, in that cigarette smoke and decreased DNA repair function work in tandem to drive the development of lung cancer. During laboratory tests, the team identified cigarette smoke exposure led to increased damage and cell death in healthy lung cells with low levels of XPC. This suggests critical molecular changes occur earlier in the disease process, before cancer has developed or been detected. DNA repair ability also declined in normal lung cells following smoke exposure.
Additionally, the researchers confirmed lower XPC gene activity in lung tumor tissue compared to normal lung tissue. This observation was consistent in the two main types of non-small cell lung cancer: adenocarcinoma and squamous cell carcinoma.
Dr. Sears said the research could help inform new prevention strategies by leveraging the role of XPC to identify high-risk individuals before lung cancer develops.
