A groundbreaking study has revealed that air pollution and certain traditional herbal medicines are linked to genetic mutations that may contribute to the development of lung cancer in individuals with little to no history of smoking. This research, published in the journal Nature on July 2, was conducted by a team of scientists from the University of California San Diego and the National Cancer Institute (NCI), part of the National Institutes of Health (NIH).
Lung cancer has long been associated with smoking, but as tobacco use declines globally, a concerning trend has emerged: an increase in lung cancer cases among non-smokers. This form of cancer disproportionately affects women, particularly those of Asian descent, and is more prevalent in East Asian countries compared to Western nations.
Genomic Evidence of Environmental Impact
The study provides compelling genomic evidence pointing to air pollution and other environmental exposures as significant factors behind this public health concern. “We’re seeing this problematic trend that never-smokers are increasingly getting lung cancer, but we haven’t understood why,” said Ludmil Alexandrov, co-senior author of the study and 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, co-senior author and epidemiologist at the NCI, emphasized the urgency of understanding lung cancer in never-smokers. “Most previous lung cancer studies have not separated data of smokers from non-smokers, which has limited insights into potential causes in those patients,” she explained. The new study aims to fill this gap by collecting global data from never-smokers and using genomics to trace potential cancer-causing exposures.
Mutational Impacts of Air Pollution
The research team analyzed lung tumors from 871 never-smokers across 28 regions with varying air pollution levels in Africa, Asia, Europe, and North America. Through whole-genome sequencing, they identified distinct patterns of DNA mutations, or mutational signatures, which serve as molecular fingerprints of past exposures.
By combining genomic data with pollution estimates from satellite and ground-level measurements of fine particulate matter, the researchers estimated individuals’ long-term exposure to air pollution. They discovered that never-smokers in more polluted environments had significantly more mutations in their lung tumors, particularly driver mutations that promote cancer development.
“Never-smokers 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 found.
Marcos Díaz-Gay, a co-first author and former postdoctoral researcher in Alexandrov’s lab, noted that while air pollution does not create a unique “air pollution mutational signature,” it increases the overall number of mutations, especially in known pathways of DNA damage.
Secondhand Smoke and Herbal Medicine Risks
Interestingly, the study 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. “If there is a mutagenic effect of secondhand smoke, it may be too weak for our current tools to detect,” said Tongwu Zhang, co-first author and investigator at the NCI.
In addition to air pollution, the researchers identified another environmental risk: aristolochic acid, a carcinogen found in some 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. This finding raises concerns about the potential cancer risk from 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.”
New Mutational Signature and Future Research
The study also uncovered a new mutational signature present in the lung cancers of most never-smokers but absent in smokers. Its cause remains unknown, opening a new area of investigation. “We see it in a majority of cases in this study, but we don’t yet know what’s driving it,” Alexandrov stated.
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, particularly among younger people who have never smoked tobacco. Additionally, the team aims to study other environmental risks, including radon and asbestos, and gather more detailed pollution data at local and individual levels.
As the research progresses, it holds the promise of unveiling new insights into the environmental factors contributing to lung cancer in non-smokers, potentially leading to more effective prevention strategies worldwide.
