Written by Charlotte Harrison, Science Writer
Cigarette smoking is the leading cause of lung cancer, but only a minority of smokers develop the disease. A new study published in Nature Genetics suggests that some smokers may be protected from lung cancer because they have mechanisms that limit the build-up of genetic mutations.
Single-cell analysis
The authors used a method – called single-cell multiple displacement amplification – that enables quantitative, genome-wide analysis of mutations in single cells. This technique avoids long-term clonal expansion, which may introduce additional mutations.
They used the technique to generate mutation profiles of normal human bronchial epithelial cells from 14 never-smokers aged 11–86 years and 19 smokers aged 44–81 years. This allowed them to quantitatively analyse the mutational burden arising from progressive age and the lifetime exposure to tobacco smoke.
The results showed that the frequency of single-nucleotide variants and small insertions and deletions increased with age in never-smokers, and the mutation frequencies were much higher in smokers. Overall, the mutation rate was 28 mutations per cell per year for never-smokers, and 91 mutations per cell per year for smokers.
It’s long been assumed that smoking leads to lung cancer by triggering DNA mutations in normal lung cells; this study was the first to prove this link.
Cancer-halting mechanisms
When the frequency of mutations was plotted against the level of smoking, the mutation frequency increased linearly with the level of smoking, but only until the level of smoking reached about 23 pack-years (which equates to smoking one pack of cigarettes each day for 23 years). After this level, there was no further increase in mutation frequency – mutational burdens in heavy smokers were no longer different from those in much lighter smokers.
“The heaviest smokers did not have the highest mutation burden,” said Simon Spivack, lead author of the study in a press release.
The authors offered two explanations for why this might occur. First, some smokers may have increased resilience to mutation induction, such as through more accurate DNA repair. Second, the increased resilience to mutation accumulation might be caused by an individual’s ability to detoxify mutagenic compounds in tobacco smoke. Indeed, two smokers in the study had polymorphisms in AKR1C2 that would help detoxify polycyclic aromatic hydrocarbons from cigarette smoke.
The findings could one day help identify smokers who are at higher risk for lung cancer. “We don’t yet know whether or not our findings will inform future diagnosis or treatment of lung cancer, but it is a step in the right direction,” Spivack said.
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