Pilar Gallego and Marcos Díaz-Gay. / Esther Sánchez. CNIO
The research was conducted by a group at the University of California in San Diego and the American National Cancer Institute. The first author is Marcos Díaz Gay, head of the new Digital Genomics Group at Spain’s National Cancer Research Centre (CNIO).
The findings, published in Nature, show for the first time the relationship between lung cancer and DNA damage caused by exposure to air pollution.
Smoking is declining in many parts of the world, but statistics warn of an increase in cases of lung cancer among non-smokers. These findings point to pollution as a possible cause.
A quarter of lung cancer cases occur in people who have never smoked. What is the cause behind these cancers? After analysing genetic alterations (mutations) in tumours found in 871 non-smokers from four continents, a study points to air pollution as one of the possible causes. The findings, published today in Nature, show for the first time the relationship between lung cancer and DNA damage caused by breathing polluted air.
The study has been led by Ludmil Alexandrov from the University of California, San Diego, and Maria Teresa Landi from the National Cancer Institute (NCI), part of the U.S. National Institutes of Health (NIH). Lead authors are Marcos Díaz Gay, head of the new Digital Genomics Group at Spain’s National Cancer Research Centre (CNIO), and Tongwu Zhang, from the NCI.
CNIO researcher Pilar Gallego García is also co-author of the paper. Gallego García and Díaz Gay have joined CNIO as part of the ‘Building the AI Generation’ programme, within the Generation D initiative, promoted by Red.es.
Recently, Díaz-Gay and Alexandrov also published another article in Nature, analysing the DNA footprint left by certain environmental agents and linking the increase in colon cancer among young people to exposure to a bacterial toxin in childhood.
More instances of lung cancer in non-smokers
Smoking is declining in many parts of the world, but global cancer statistics warn of an increase in lung cancer cases among non-smokers. This is a type of cancer that affects especially women of Asian origin and tends to be more common in East Asia than in Western countries.
“We are seeing this worrying trend that those who have never smoked are increasingly developing lung cancer, and we don’t understand why. Our research shows that air pollution is closely related to the same kind of DNA mutations we often associate with smoking,” says Alexandrov.
“It’s an urgent and growing global problem,” adds Landi, an epidemiologist at the NCI’s Division of Cancer Epidemiology and Genetics. “Most previous studies on lung cancer do not differentiate between smoking and non-smoking data, which has limited the identification of risk factors in these patients. Our study collects data from non-smokers around the world, and uses genomics to track what exposures may be causing these cancers.”
Previous studies have demonstrated an epidemiological link between air pollution and lung cancer in non-smokers, but new research goes further by showing a genomic link.
Searching for ‘mutational signatures’ in tumours around the world
The team analysed lung tumours from 871 people who had never smoked and live in 28 regions across Africa, Asia, Europe and North America, each with varying levels of air pollution. By sequencing the entire genome of these tumours, they identified distinct patterns of DNA mutations—known as mutational signatures—which act as molecular footprints of past environmental exposures.
When these genomic data were combined with air pollution estimates (based on satellite and ground-level measurements of fine particulate matter), the researchers found that non-smokers living in more polluted areas had a significantly higher number of mutations in their lung tumours. For example, these people had 3.9 times more smoking-related mutations and 76% times more ageing-related mutations.
This does not mean that pollution causes a unique “mutational signature of air pollution” per se, but rather it increases the total number of mutations, explains Díaz-Gay, a former postdoctoral researcher at Alexandrov’s lab.
More mutations and shorter telomeres
“We are seeing that air pollution is associated with an increase in somatic mutations, including those that correspond to known mutational signatures attributed to smoking and ageing,” says Díaz Gay.
The researchers also observed that the more exposed a person was to pollution, the more mutations there were in their lung cancer. They also presented shorter telomeres – the protective caps at the ends of chromosomes – a sign of accelerated cellular ageing.
Aristolochic acid and unknown carcinogens
In addition to air pollution, the researchers have identified another environmental risk: aristolochic acid, a carcinogen present in certain traditional medicinal herbs. A specific mutational signature linked to aristolochic acid was found almost exclusively in lung cancer cases of Taiwanese individuals who had never smoked.
Although aristolochic acid has previously been linked to cancers of the bladder, gastrointestinal tract, kidneys and liver through ingestion, this is the first study to provide evidence that it may also contribute to lung cancer.
The team also identified a new mutational signature that appeared more frequently in the lung cancers of people who had never smoked, compared to those who had. Its cause remains unknown: it does not correlate with air pollution or any other known environmental exposure. “We found it in the majority of cases in this study, but we still don’t know what’s causing it,” said Alexandrov. “This appears to be something entirely different, and it opens up a whole new area of research.”
Next steps: analyse mutations related to marijuana use and vaping
Looking ahead, these researchers are expanding their study to include lung cancer cases among non-smokers in Latin America, the Middle East and more regions of Africa. They are also focusing their attention on other potential risks. One of them is the use of marijuana and e-cigarettes, especially among young people who have never smoked tobacco.
The new research group at CNIO will also study other environmental risks, such as radon and asbestos, in collaboration with other groups in Spain. In addition, they will collect more detailed data on pollution at local and individual levels.
An opportunity for Generation D.
The Building the AI Generation programme, which has made it possible for Díaz-Gay to return to Spain and to hire Gallego, is part of the Generation D initiative, promoted by Red.es, an initiative attached to the Spanish Department for Digital Transformation and Public Service through the State Secretariat for Digitalisation and Artificial Intelligence.
With a budget of 120 million euros, the Building the AI Generation programme has allowed 374 research contracts to be awarded in relation to artificial intelligence and digital transformation in all scientific and research areas. Its actions are financed by the Recovery, Transformation and Resilience Plan through the Next Generation funds of the European Union, within Investment Framework 4, Component 19 of the National Digital Skills Plan.
About the National Cancer Research Centre (CNIO)
The National Cancer Research Centre (CNIO) is a public research centre under the Department of Science, Innovation and Universities. It is the largest cancer research centre in Spain and one of the most important in Europe. It includes around five hundred scientists, along with support staff, who are working to improve the prevention, diagnosis and treatment of cancer.
Reference article
DOI 10.1038/s41586-025-09219-0