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The Mystery of Why So Many Lifelong Smokers Never Get Lung Cancer May Be Solved

26 MAY 2022

Smoking cigarettes is the number one risk factor for lung cancer, with tobacco products causing up to 90 percent of lung cancer deaths in the United States. 

Without a doubt, the safest way to protect yourself against lung cancer is to avoid smoking cigarettes, and yet, at the same time, it's also true that not all lifelong smokers are doomed to develop cancer.

 

In fact, the vast majority don't. Scientists have long wondered why, and a new study adds weight to the idea that genetics has a role to play.

Among people who smoke but never develop lung cancer, researchers found an inherent advantage. The cells that line their lungs appear to be less likely to mutate over time.

The findings suggest that DNA repair genes are more active among some individuals, which can protect against cancers arising, even when cigarettes are regularly smoked.

The study made use of genetic profiles taken from the bronchi of 14 never-smokers and 19 light, moderate, and heavy smokers.

Surface cells collected from the lungs of the participants were sequenced individually to measure mutations in their genomes.

"These lung cells survive for years, even decades, and thus can accumulate mutations with both age and smoking," explains epidemiologist and pulmonologist Simon Spivack from the Albert Einstein College of Medicine.

"Of all the lung's cell types, these are among the most likely to become cancerous."

According to the authors, the findings "unequivocally demonstrate" that mutations in the human lung increase with natural age, and among smokers, the DNA damage is even more significant.

 

Tobacco smoke has long been associated with triggering DNA damage in the lung, but the new study found not all smokers are in the same boat.

While the amount that someone smoked was linked to an increase in cell mutation rates, after the equivalent of about 23 years of smoking a pack a day, that risk plateaus.

"The heaviest smokers did not have the highest mutation burden," says 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 findings could help explain why 80 to 90 percent of lifelong smokers never develop lung cancer. It could also help explain why some people who never smoke at all do develop the tumors.

While toxic tobacco smoke seems to trigger extra cell mutations in the lung, whether these mutations develop into tumors is dependent on how well the body can repair DNA or reduce DNA damage.

 

Genes concerned with DNA repair can be inherited or acquired, and the silencing of repair genes has been associated with tumor development in previous research.

Genes aren't the only factors influencing a person's cancer risk. Environmental factors like diet can also influence nutrients in the body that impact tumor development.

What makes an individual's body better at repairing DNA is still up for debate and is likely complicated, but the new findings suggest this process is closely tied to lung cancer development.

"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," says geneticist Jan Vijg.

The study was published in Nature.