Now, a study published on July 2 in Nature has uncovered compelling genomic evidence that points to air pollution—and other environmental exposures—as a potential major factor behind this growing public health concern. The study was jointly led by researchers at the University of California San Diego and the National Cancer Institute (NCI), part of the National Institutes of Health (NIH).
“We’re seeing this problematic trend that never-smokers are increasingly getting lung cancer, but we haven’t understood why,” said study co-senior author Ludmil Alexandrov, professor of bioengineering and cellular and molecular medicine at UC San Diego, and member of UC San Diego Moores Cancer Center. “Our research shows that air pollution is strongly associated with the same types of DNA mutations we typically associate with smoking.”
“This is an urgent and growing global problem that we are working to understand regarding never-smokers,” said Maria Teresa Landi, epidemiologist in the Division of Cancer Epidemiology and Genetics at the NCI and co-senior author of the study. “Most previous lung cancer studies have not separated data of smokers from non-smokers, which has limited insights into potential causes in those patients. We have designed a study to collect data from never-smokers around the world and use genomics to trace back what exposures might be causing these cancers.”
And while previous studies in the literature have shown an epidemiological link between air pollution and lung cancer in never-smokers, this new research goes further by showing a genomic link.
Mutational effects of air pollution
The team analyzed lung tumors from 871 never-smokers living in 28 regions with different levels of air pollution across Africa, Asia, Europe and North America. Using whole-genome sequencing, the researchers identified distinct patterns of DNA mutations—known as mutational signatures—that act like molecular fingerprints of past exposures.
By combining these genomic data with pollution estimates based on satellite and ground-level measurements of fine particulate matter, the researchers were able to estimate individuals’ long-term exposure to air pollution. They found that never-smokers living in more polluted environments had significantly more mutations in their lung tumors, particularly driver mutations—which directly promote cancer development—and mutational signatures linked to cancer—which serve as a record of all past mutagenic exposures. For example, these individuals had a 3.9-fold increase in a mutational signature linked to tobacco smoking and a 76% increase in another signature linked to aging.
This doesn’t mean that pollution causes a unique “air pollution mutational signature” per se, noted study co-first author Marcos Díaz-Gay, a former postdoctoral researcher in Alexandrov’s lab who is now a junior group leader at the Spanish National Cancer Research Center (CNIO) in Madrid, Spain. Rather, it increases the overall number of mutations, particularly in known pathways of DNA damage. “What we see is that air pollution is associated with an increase in somatic mutations, including those that fall under known mutational signatures attributed to tobacco smoking and aging,” said Díaz-Gay.
The researchers also noted a dose-response relationship: the more pollution someone was exposed to, the more mutations were found in their lung tumors. These tumors also had shorter telomeres—the protective caps on the ends of chromosomes—which is a sign of accelerated cellular aging.
Surprising finding from secondhand smoke exposure
In contrast, the researchers did not find a strong genetic correlation with secondhand smoke. Lung tumors of never-smokers exposed to secondhand smoke showed only a slight increase in mutations, along with shorter telomeres, but no distinct mutational signatures or driver mutations. While exposure to secondhand smoke is a known cancer risk, its mutational effect was far less pronounced than that seen with air pollution. “If there is a mutagenic effect of secondhand smoke, it may be too weak for our current tools to detect,” said study co-first author Tongwu Zhang, an Earl Stadtman Investigator in the Biostatistics Branch of the NCI. “However, its biological effects are still evident in the significant telomere shortening.”
The researchers acknowledged that their analysis could be further limited by the complexity of measuring secondhand smoke exposure. “It’s difficult to get that kind of information because it depends on various factors such as amount of time one was exposed; how far one was from exposure; and how often one shared a space with someone else who smoked, for example,” said Díaz-Gay.
Risk found from herbal medicine
In addition to air pollution, researchers identified another environmental risk: aristolochic acid, a carcinogen found in certain traditional Chinese herbal medicines. A specific mutational signature linked to aristolochic acid was found almost exclusively in lung cancer cases of never-smokers from Taiwan. Though aristolochic acid has previously been linked to bladder, gastrointestinal, kidney and liver cancers from ingestion, this is the first study to report evidence that it may contribute to lung cancer. The researchers suspect that these cases may arise from inhalation of traditional Chinese herbal medicines, but more data are needed to support their hypothesis.
“This raises new concerns about how traditional remedies might unintentionally raise cancer risk,” said Landi. “It also presents a public health opportunity for cancer prevention—particularly in Asia.”
New signature, new questions
In another intriguing discovery, the team identified a new mutational signature that appears in the lung cancers of most never-smokers but is absent in smokers. Its cause remains unknown—it did not correlate with air pollution or any other known environmental exposure. “We see it in a majority of cases in this study, but we don’t yet know what’s driving it,” said Alexandrov. “This is something entirely different, and it opens up a whole new area of investigation.”
Next steps
Moving forward, the researchers are expanding their study to include lung cancer cases of never-smokers from Latin America, the Middle East and more regions of Africa. The researchers are also turning their attention to other potential risks. One focus is on marijuana and e-cigarette use, particularly among younger people who have never smoked tobacco. The team is investigating whether these exposures may also contribute to mutational changes in lung tissue. They also aim to study other environmental risks—such as radon and asbestos—as well as gather more detailed pollution data at local and individual levels.
Full study: “The mutagenic forces shaping the genomes of lung cancer in never smokers.”
This work was supported by the Intramural Research Program of the National Cancer Institute, part of the National Institutes of Health (project ZIACP101231); NIH grants R01ES032547-01, R01CA269919-01, and 1U01CA290479-01; a Packard Fellowship for Science and Engineering; and UC San Diego Sanford Stem Cell Institute.
Disclosures: Ludmil B. Alexandrov is a co-founder, CSO, scientific advisory member and consultant for io9. Alexandrov has equity in and receives income from io9. The terms of this arrangement have been reviewed and approved by the University of California San Diego in accordance with its conflict of interest policies. Alexandrov is also a compensated member of the scientific advisory board of Inocras. Alexandrov’s spouse is an employee of Biotheranostics. Alexandrov and study co-author Erik N. Bergstrom declare a U.S. provisional patent application filed with UC San Diego with serial numbers 63/269,033. Alexandrov also declares U.S. provisional applications filed with UC San Diego with serial numbers: 63/366,392; 63/289,601; 63/483,237; 63/412,835; and 63/492,348. Alexandrov is also an inventor of a U.S. Patent 10,776,718 for source identification by non-negative matrix factorization. Alexandrov and study co-first author Marcos Díaz-Gay further declare a European patent application with application number EP25305077.7. Study co-author Soo-Ryum Yang has received consulting fees from AstraZeneca, Sanofi, Amgen, AbbVie and Sanofi; and received speaking fees from AstraZeneca, Medscape, PRIME Education and Medical Learning Institute. All other authors declare that they have no competing interests.
