A groundbreaking study has unveiled a significant link between air pollution, traditional herbal medicines, and genetic mutations that may lead to lung cancer in individuals with little to no history of smoking. This revelation challenges the long-held belief that lung cancer is predominantly a smoker’s disease. As tobacco use declines globally, a troubling trend has emerged: an increase in lung cancer cases among non-smokers, particularly affecting women of Asian descent and more prevalent in East Asian countries compared to Western nations.
The study, published on July 2 in the journal Nature, presents compelling genomic evidence suggesting that environmental exposures are significant contributors to this growing public health issue. The research was spearheaded by teams from the University of California San Diego and the National Cancer Institute (NCI), part of the National Institutes of Health (NIH).
New Genomic Insights into Lung Cancer
“We’re seeing this problematic trend that never-smokers are increasingly getting lung cancer, but we haven’t understood why,” explained Ludmil Alexandrov, a co-senior author of the study and a professor of bioengineering and cellular and molecular medicine at UC San Diego. “Our research shows that air pollution is strongly associated with the same types of DNA mutations we typically associate with smoking.”
Maria Teresa Landi, an epidemiologist at the NCI and co-senior author, emphasized the urgency of this issue. “This is an urgent and growing global problem that we are working to understand regarding never-smokers,” she stated. “Most previous lung cancer studies have not separated data of smokers from non-smokers, which has limited insights into potential causes in those patients.”
The study’s findings extend beyond epidemiological links, providing a genomic perspective on how air pollution impacts DNA mutations in non-smokers. The research involved analyzing lung tumors from 871 never-smokers across 28 regions with varying pollution levels, identifying distinct patterns of DNA mutations known as mutational signatures.
Mutational Effects of Air Pollution
Utilizing whole-genome sequencing, the researchers identified mutational signatures that act as molecular fingerprints of past exposures. By integrating these genomic data with pollution estimates from satellite and ground-level measurements, they estimated individuals’ long-term exposure to air pollution. The results revealed that never-smokers in more polluted environments had significantly more mutations in their lung tumors, particularly driver mutations and mutational signatures linked to cancer.
“Never-smokers living in polluted areas had a 3.9-fold increase in a mutational signature linked to tobacco smoking and a 76% increase in another signature linked to aging,” the study revealed.
Marcos Díaz-Gay, a co-first author of the study, noted that while pollution does not create a unique “air pollution mutational signature,” it increases the overall number of mutations, particularly in known pathways of DNA damage. The researchers also observed a dose-response relationship: higher pollution exposure correlated with more mutations and shorter telomeres, indicating accelerated cellular aging.
Secondhand Smoke and Herbal Medicine Risks
Interestingly, the study found a weaker genetic correlation with secondhand smoke. Lung tumors of never-smokers exposed to secondhand smoke showed only a slight increase in mutations, with no distinct mutational signatures or driver mutations. “If there is a mutagenic effect of secondhand smoke, it may be too weak for our current tools to detect,” said Tongwu Zhang, a co-first author and investigator at the NCI.
Beyond air pollution, the research identified aristolochic acid—a carcinogen found in certain traditional Chinese herbal medicines—as another environmental risk. A specific mutational signature linked to aristolochic acid was found almost exclusively in lung cancer cases of never-smokers from Taiwan. This finding raises concerns about the potential cancer risk posed by traditional remedies.
“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.”
Unexplained Mutational Signatures
In a surprising discovery, the researchers identified a new mutational signature present in the lung cancers of most never-smokers but absent in smokers. The cause of this signature remains unknown, and it did not correlate with any 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.”
Future Directions and Broader Implications
Looking ahead, the researchers plan to expand their study to include lung cancer cases of never-smokers from Latin America, the Middle East, and more regions of Africa. They are also exploring other potential risks, such as marijuana and e-cigarette use among younger non-smokers, and investigating whether these exposures contribute to mutational changes in lung tissue.
Additionally, the team aims to study other environmental risks, including radon and asbestos, and to gather more detailed pollution data at local and individual levels. This comprehensive approach could provide deeper insights into the environmental factors contributing to lung cancer in never-smokers and inform public health strategies for prevention and intervention.
