Lung cancer cases are on the rise in non-smokers around the world, and air pollution could be an insidious, contributing factor.
A genome study has now found that outdoor smog and soot are strongly associated with DNA mutations related to lung cancer – including known drivers seen in smokers, and new ones unique to non-smokers.
The more pollution someone was exposed to, the more mutations scientists found in their lung tumors.
The findings don't mean that air pollution is directly causing lung cancer, but they do contribute to evidence suggesting that possibility.
Related: Geneticists Just Got Closer to The Sources of Lung Cancer in People Who Never Smoked
"We're seeing this problematic trend that never-smokers are increasingly getting lung cancer, but we haven't understood why," explains biomolecular scientist Ludmil Alexandrov from the University of California San Diego (UCSD).
"Our research shows that air pollution is strongly associated with the same types of DNA mutations we typically associate with smoking."
The extensive international analysis examined the cancer genomes of 871 individuals from four continents, all of whom had lung cancer despite never having smoked and who had not yet received cancer treatment.
Those who lived in regions with high levels of air pollution were significantly more likely to have TP53 mutations, EGFR mutations, and shorter telomeres.
Abnormal TP53 and EGFR genes are hallmarks of lung cancers, especially those driven by the SBS4 DNA mutation, and shorter telomeres are linked to accelerated aging.
In the current study, non-smokers who lived in areas with higher air pollution were nearly four times more likely to exhibit SBS4 signatures as those who lived in regions with cleaner air.
By contrast, exposure to secondhand smoke, which is a known cancer risk, showed only a slight increase in genetic mutations.
"If there is a mutagenic effect of secondhand smoke, it may be too weak for our current tools to detect," says geneticist Tongwu Zhang from the US National Cancer Institute (NCI).
Not so for air pollution or tobacco smoking: both were strongly linked to DNA mutations.
Today in the United States, people who have never smoked or who have smoked fewer than 100 cigarettes in their lives make up about 10 to 20 percent of lung cancer cases.
Scientists have long suspected that air pollution could be a contributing factor, but exactly how fine particulate matter in the air compares to tobacco smoking or secondhand smoke exposure remains unclear.
Some studies suggest that breathing polluted air is on par with smoking a pack a day, and yet these conclusions are mostly based on observational analyses.
The current study digs further by looking at some of the molecular mechanisms that may be at play. It compared the lung cancer genomes of the 871 non-smokers with tumors from 345 smokers, to find similarities and differences.
The majority of non-smokers with lung cancer had adenocarcinomas (the most common type of lung cancer), and nearly 5 percent of those tumors showed the SBS4 mutational signature.
In addition, 28 percent of non-smokers showed a new signature called SBS40a, which wasn't found in tobacco smokers. Strangely, the cause of this particular mutational driver was unknown, but doesn't seem to be environmental in nature.
"We see it in a majority of cases in this study, but we don't yet know what's driving it," says Alexandrov. "This is something entirely different, and it opens up a whole new area of investigation."
The current research relied only on regional air pollution levels, which means it can't say how much any one individual was directly exposed to fine particulate matter in the air. Participants who said they had never smoked may have also smoked more than reported.
These limitations notwithstanding, the overall findings align with other evidence indicating that soot or smog may trigger tumor growth in a similar way to cigarette chemicals.
"This is an urgent and growing global problem that we are working to understand regarding never-smokers," says epidemiologist Maria Teresa Landi from the NCI.
The team now hopes to expand their study to include cancer genomes from a more diverse, global cohort.
The study was published in Nature.