Even though cigarette smoking is by far the main cause of lung cancer, only a minority of smokers develop the disease. A study reported in Nature Genetics suggests that some smokers may have robust mechanisms that protect them from lung cancer by keeping mutations in check. The findings could help identify those smokers who face an increased risk for the disease and therefore warrant especially close 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,” said Simon Spivack, MD, MPH, a co-senior author of the study.
For a long time, it has been assumed that smoking leads to lung cancer by triggering DNA mutations in normal lung cells. “But that could never be proven until our study, since there was no way to accurately quantify mutations in normal cells,” said Dr Jan Vijg, a study co-senior author. Dr Vijg overcame that obstacle a few years ago by developing an improved method for sequencing the entire genomes of individual cells.
Single-cell whole-genome sequencing methods can inadvertently introduce sequencing errors difficult to distinguish from true mutations – a major flaw when looking for rare and random mutations. To get around this, Dr Vijg developed a sequencing technique called single-cell multiple displacement amplification (SCMDA).
The researchers used SCMDA to compare the mutational landscape of normal lung epithelial cells from two types of people: 14 never-smokers, ages 11 to 86; and 19 smokers, ages 44 to 81, who had smoked a maximum of 116 pack-years. (One pack-year of smoking equals 1 pack of cigarettes smoked per day for one year.) The cells were collected from patients who were undergoing bronchoscopy for diagnostic tests unrelated to cancer. “These lung cells survive for years, even decades, and thus can accumulate mutations with both age and smoking,” said Dr Spivack. “Of all the lung’s cell types, these are among the most likely to become cancerous.”
The researchers found that mutations accumulated in the lung cells of non-smokers as they age, and significantly more mutations were found in the lung cells of the smokers. “This experimentally confirms that smoking increases lung cancer risk by increasing the frequency of mutations, as previously hypothesised,” said Dr Spivack. “This is likely one reason why so few non-smokers get lung cancer, while 10% to 20% of lifelong smokers do.”
The study also revealed that the number of cell mutations detected in lung cells increased in a straight line with the number of pack years of smoking and, presumably, so did the lung cancer risk. However, the cell mutations stopped rising after 23 pack-years of exposure.
“The heaviest smokers did not have the highest mutation burden,” said Dr Spivack. “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.”
The finding has led to a new research direction. “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,” said Dr Vijg.
