Lung Cancer Risk: Study Identifies Potential Mechanism in Patients With a Smoking History

By: Joshua D. Madera, MS
Posted: Wednesday, July 6, 2022

The association between smoking and an increased risk for lung cancer may be due to an increased frequency of somatic mutations, according to a study published in Nature Genetics. However, heavy smokers may possess an intrinsic mechanism to reduce the impact of these somatic mutations by increasing the accuracy of DNA repair mechanisms or reducing smoke-induced DNA damage, explained Simon D. Spivack, MD, MPH, of Albert Einstein College of Medicine, Bronx, New York, and colleagues.

“The heaviest smokers did not have the highest mutation burden,” said Dr. Spivack in an institutional press release. “Our data suggest that these individuals may have survived for so long in spite of their heavy smoking because they managed to suppress further mutation accumulation.”

A total of 33 patients undergoing bronchoscopy at Montefiore Medical Center were recruited for the study. If patients had a diagnosis of carcinoma, the brush biopsy specimen was taken from a contralateral site. All patients were between 11 and 86 years old, with variable smoking histories from never-smokers to those with a smoking history of 116-pack years. Patient samples were subjected to single-cell, whole-genome sequencing of proximal bronchial basal cells.

In never-smokers, there was an increased frequency of small insertions and deletions, and single-nucleotide variants as chronologic age increased. Among smokers, there was a significant elevation in mutation frequencies. In addition, the relationship between cancer risk and mutation frequency demonstrated a linear increase until approximately 23-pack years. After this point, no additional increases in mutation frequency were observed, suggesting the role of individual selection for mutation avoidance. Furthermore, both age and smoking status aligned with established lung cancer–defined mutation signatures. Moreover, enrichment for somatic mutation was not observed in lung cancer driver genes.

“This study provides a rational basis to further evaluate the nature of these intrinsic lung cancer risk factors that modulate mutation susceptibility of normal bronchial cells,” the study investigators concluded.

Disclosure: For full disclosures of the study authors, visit nature.com.

Nature Genetics