Genetic mutations reveal why many smokers never get lung cancer

NEW YORK — The link between smoking and lung cancer is so strong, most cigarette packs even warn users right on the label. So, how do so many life-long smokers never so much as develop a cough? Researchers from the Albert Einstein College of Medicine are offering up a potential new explanation for this phenomenon. Scientists report certain people may have robust defenses that offer extra protection against lung cancer by limiting mutations.

This theory is intriguing on two levels. To start, it provides an explanation as to why the majority of smokers don’t develop lung cancer. Alternatively, however, this work may also help identify individuals who are at an increased risk of developing lung cancer and need closer monitoring.

“This may prove to be an important step toward the prevention and early detection of lung cancer risk and away from the current herculean efforts needed to battle late-stage disease, where the majority of health expenditures and misery occur,” says co-senior study author Simon Spivack, M.D., M.P.H., professor of medicine, of epidemiology & population health, and of genetics at Einstein, and a pulmonologist at Montefiore Health System, in a university release.

Doctors and scientists alike have long believed that smoking causes lung cancer by sparking various DNA mutations within otherwise normal lung cells.

“But that could never be proven until our study, since there was no way to accurately quantify mutations in normal cells,” notes co-senior study author Jan Vijg, Ph.D., professor and chair of genetics, professor of ophthalmology and visual sciences, and the Lola and Saul Kramer Chair in Molecular Genetics at Einstein.

New gene sequencing method opens the door to study mutations

Single-cell whole-genome sequencing methods have been shown to induce sequencing errors that are particularly hard to distinguish from true mutations. This makes analyzing cells containing rare and random mutations much more difficult. Dr. Vijg largely solved this research problem a few years ago by developing a new, improved method of sequencing the entire genomes of individual cells. According to the scientific journal Nature Methods in 2017, this new method successfully accounts for and subsequently reduces sequencing errors.

This study’s authors utilized Dr. Vijg’s improved method (SCMDA) to analyze and compare the mutational landscape of normal lung epithelial cells (the cells that line the lung) from two distinct groups: 14 people who never smoked (ages 11-86) and 19 smokers (ages 44-81), who smoked a maximum of 116 “pack years.”

For this study, “one pack year” of smoking equaled one pack of cigarettes smoked per day for a single year. The team gathered cells from patients undergoing bronchoscopy for non-cancer related diagnostic tests.

“These lung cells survive for years, even decades, and thus can accumulate mutations with both age and smoking,” Dr. Spivack adds. “Of all the lung’s cell types, these are among the most likely to become cancerous.”

Heavy smokers don’t have ‘the highest mutation burden’

The analysis revealed mutations (single-nucleotide variants, as well as small insertions and deletions) built up in the lung cells of non-smokers as they grew older. However, significantly more mutations were present within the lung cells of smokers.

“This experimentally confirms that smoking increases lung cancer risk by increasing the frequency of mutations, as previously hypothesized,” Dr. Spivack adds. “This is likely one reason why so few non-smokers get lung cancer, while 10% to 20% of lifelong smokers do.”

The study also found that the amount of cell mutations seen in lung cells increased “in a straight line” with number of pack years spent smoking. This suggests, presumably, lung cancer risk increased at the same rate. Despite those findings, the observed rise in cell mutations stopped after 23 pack years of smoke exposure.

“The heaviest smokers did not have the highest mutation burden,” Dr. Spivack explains. “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. This leveling off of mutations could stem from these people having very proficient systems for repairing DNA damage or detoxifying cigarette smoke.”

“We now wish to develop new assays that can measure someone’s capacity for DNA repair or detoxification, which could offer a new way to assess one’s risk for lung cancer,” Dr. Vijg concludes.

The study is published in the journal Nature Genetics.

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