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Smoking Induces Mutations in Lung Tissue but Quitting Helps Replenish Healthy Cells

NEW YORK – While many cells from the lungs of former smokers harbor genetic mutations, a sizeable portion of their lung cells have a mutational burden that more closely resembles that of never-smokers, a new study has found. Quitting could thus not only prevent further damage from being done but also lead healthy cells to repopulate the lungs.

About 1.1 billion people across the world smoke, according to the World Health Organization, and smokers have a 30-fold higher risk of developing lung cancer than non-smokers. While scientists have studied how tobacco smoke affects the genomes of lung cancer cells, less is known about how smoking affects normal lung cells.

Researchers led by the Wellcome Sanger Institute's Peter Campbell have now isolated single cells from the lungs of children as well as from adults who are never, former, and current smokers to grow colonies for sequencing analysis. As they reported Wednesday in Nature, the researchers found that current and former smokers typically had higher numbers of point mutations and other genetic alterations than non-smokers. But about 40 percent of cells isolated from former smokers looked more like those of people who have never smoked.

"People who have smoked heavily for 30, 40, or more years often say to me that it's too late to stop smoking — the damage is already done," Campbell said in a statement. "What is so exciting about our study is that it shows that it's never too late to quit — some of the people in our study had smoked more than 15,000 packs of cigarettes over their life, but within a few years of quitting, many of the cells lining their airways showed no evidence of damage from tobacco."

He and his colleagues collected normal bronchial epithelium samples from three children, four never-smokers, six former smokers, and three current smokers. They dissociated cells from these samples and flow-sorted them to generate single cell-derived colonies. They then sequenced these colonies to an average 16X coverage. In all, they generated catalogs of somatic mutations based on whole-genome sequencing data of 632 single bronchial cells.

Overall, exposure to tobacco smoke increased cells' mutational burdens. On average, current smokers had an additional 5,300 point mutations and former smokers an additional 2,300 point mutations per cell, and driver mutations were more common among patients with a history of smoking. Mutational burden also increased with age.

The mutational signatures present also varied between these groups. Three substitution signatures — SBS-4, SBS-16, and a new mutational signature dubbed Sig-B — were only found among current or former smokers, while other mutational signatures like SBS-5 were associated with age.

There was also considerable variability in mutational burden from cell to cell, even among cells from the same individual. While more cells from current or former smokers had higher mutational rates than cells from never-smokers, a portion of cells from former smokers had a mutational burden that was near normal. These near-normal cells had a fourfold higher frequency among former smokers and accounted for between 20 percent and 40 percent of the cells studied. These cells also had a lower portion of SBS-4 mutations and longer telomeres than cells from the same patient with higher mutational burdens.

This finding could in part account for why ex-smokers have a decreasing risk — though still elevated when compared to never-smokers — of developing lung cancer after they quit than current smokers, wrote the Van Andel Institute's Gerd Pfeifer in a related commentary in Nature

But the cell biology and mechanisms behind this finding are as yet unclear. The study, he wrote, "has shed light on how the protective effect of smoking cessation plays out at the molecular level in human lung tissue and raises many interesting questions worthy of future investigation."