The benefits of quitting

It's well known that giving up smoking can decrease smokers' chances of developing lung cancer, but new research has shown that that is not simply due to a lack of ongoing exposure to carcinogens. A recent study—part of the £20 million Mutographs of Cancer project, a Cancer Research UK Grand Challenge initiative—found that ex-smokers present with more genetically healthy lung cells that lack mutations that could lead to cancer. This work was a joint effort between scientists from the Wellcome Sanger Institute, University College London (UCL) and collaborators, and was published in Nature in an article titled “Tobacco smoking and somatic mutations in human bronchial epithelium.”

This work looked at lung and bronchial cells, with the research team conducting whole-genome sequencing on 632 colonies “derived from single bronchial epithelial cells across 16 subjects,” which included current smokers, ex-smokers and individuals who had never smoked, as noted in the paper. There are “more than 60 carcinogens in cigarette smoke that directly damage and mutate DNA,” the authors report, and in this work, “Tobacco smoking was the major influence on mutational burden, typically adding from 1,000 to 10,000 mutations per cell; massively increasing the variance both within and between subjects; and generating several distinct mutational signatures of substitutions and of insertions and deletions.”

These extra mutations weren't limited to cancerous cells, either; the research team reported that even in non-cancerous cells, more than nine out of every 10 lung cells in active smokers presented with up to 10,000 extra mutations compared to those of non-smokers. In addition, more than a quarter of the damaged lung cells presented with at least one cancer-driver mutation that predisposes a cell for aberrant growth.

“Our study is the first time that scientists have looked in detail at the genetic effects of smoking on individual healthy lung cells. We found that even these healthy lung cells from smokers contained thousands of genetic mutations. These can be thought of as mini time-bombs waiting for the next hit that causes them to progress to cancer. Further research with larger numbers of people is needed to understand how cancer develops from these damaged lung cells,” said Dr. Kate Gowers, joint first author from UCL.

On the positive side, however, the study also showed that in ex-smokers, there was an ample population of cells lining the airways that resembled lung cells from individuals who had never smoked—specifically, they presented with much less genetic damage from cigarette carcinogens and a low risk of becoming cancerous. When compared to active smokers, ex-smokers had four times more of those healthy cells, comprising up to 40 percent of the total lung cells in ex-smokers.

“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,” remarked Dr. Peter Campbell of the Wellcome Sanger Institute, joint senior author. “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.”

A Nature commentary article on the study—penned by Gerd P. Pfeifer and titled “Smoke signals in the DNA of normal lung cells”—noted that the authors found that age and smoking status both impact mutational burden, though to very different degrees. With each added year, cells generally presented with roughly 22 additional single nucelotide mutations; “being a former smoker added another 2,330, and being a current smoker added 5,300 point mutations per cell on average,” Pfeifer cited. In terms of specific mutations of interest, the researchers reported that some lung cells presented with mutations in genes known to be driver mutations in squamous cell carcinomas, such as TP53 and NOTCH1.

In addition to providing new answers about lung cancer, Pfeifer pointed out that this study also brings up further questions: “Why do ex-smokers still have a substantial fraction of highly mutated cells that can proliferate, at least when grown in vitro? Any short-lived cells that were exposed to carcinogens during their proliferation should have vanished many years after the cessation of smoking. This raises the question of whether there are long-lived differentiated cells in the lung that carry a high mutational burden, and whether these cells can resume proliferation, perhaps because of the plasticity (the ability to change cellular identity) of lung cells.”

“A future challenge will be to understand the cell biology of the mechanisms underlying these observations. Perhaps one day it will be possible to develop ways to boost the population of lung cells with few mutations in ex-smokers,” Pfeifer concluded.