Why most smokers don’t get lung cancer

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Cigarette smoking is overwhelmingly the main cause of lung cancer, yet only a minority of smokers develop the disease.

Scientists from the Albert Einstein College of Medicine found that some smokers may have robust mechanisms that protect them from lung cancer by limiting mutations.

The findings could help identify those smokers who face an increased risk for the disease and therefore warrant especially close monitoring.

The research is published in Nature Genetics and was conducted by Simon Spivack et al.

It’s long been assumed that smoking leads to lung cancer by triggering DNA mutations in normal lung cells.

Single-cell whole-genome sequencing methods can introduce sequencing errors that are hard to distinguish from true mutations—a serious flaw when analyzing cells containing rare and random mutations.

The team solved this problem by developing a new sequencing technique called single-cell multiple displacement amplification (SCMDA).

In the study, the team used SCMDA to compare the mutational landscape of normal lung epithelial cells (i.e., cells lining the lung) 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.

The cells were collected from patients who were undergoing bronchoscopy for diagnostic tests unrelated to cancer.

The team found that mutations (single-nucleotide variants and small insertions and deletions) accumulated in the lung cells of non-smokers as they age—and that much more mutations were found in the lung cells of the smokers.

This confirms that smoking increases lung cancer risk by increasing the frequency of mutations, as previously hypothesized.

This is likely one reason why so few non-smokers get lung cancer, while 10% to 20% of lifelong smokers do.

The team also found the number of cell mutations detected in lung cells increased in a straight line with the number of pack years of smoking—and, presumably, the risk for lung cancer increased as well.

But interestingly, the rise in cell mutations halted after 23 pack years of exposure.

The team found 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 team now wishes 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.

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