One-quarter of lung cancer cases occur in people who have never smoked. What is the cause of these cancers? A study analyzing genetic alterations in tumors of 871 non-smokers from four continents points to air pollution as one of the possible causes. The research, published today in Nature, shows for the first time the relationship between lung cancer and the damage caused to DNA by breathing polluted air.
The work is jointly led by Ludmil Alexandrov from the University of California in San Diego, and Maria Teresa Landi from the National Cancer Institute (NCI) of the U.S. National Institutes of Health (NIH). The first signatories are Marcos Díaz Gay, head of the new Digital Genomics Group at the Spanish National Cancer Research Centre (CNIO), and Tongwu Zhang from the NCI. Also, co-author is CNIO researcher Pilar Gallego García.
Recently, Díaz-Gay and Alexandrov also published in Nature another analysis of the footprint left on DNA by certain environmental agents, linking the increase in colorectal cancer in young people to exposure to a bacterial toxin in childhood.
Tobacco consumption is decreasing in many parts of the world, but global cancer statistics warn of an increase in lung cancer cases in people who have never smoked. It is a type of cancer that particularly affects women of Asian origin and tends to be more common in East Asia than in Western countries.
"We observe this concerning trend of non-smokers developing more and more lung cancer, and we do not understand why. Our research shows that air pollution is closely related to the same type of DNA mutations that we usually associate with smoking," says Alexandrov.
For Landi, an epidemiologist at the NCI's Division of Cancer Epidemiology and Genetics, this is an urgent and growing global problem. "Most previous studies on lung cancer do not differentiate between data from smokers and non-smokers, which has limited the identification of risk factors in these patients. Our study collects data from non-smokers worldwide and uses genomics to track what exposures could be causing these cancers."
Previous studies demonstrated an epidemiological link between air pollution and lung cancer in non-smokers, but the new research goes further by showing a genomic link.
Mutational signatures around the world
The team analyzed lung tumors from 871 people who had never smoked and lived in 28 regions of Africa, Asia, Europe, and North America with varying levels of air pollution. By sequencing the entire genome, they identified different patterns of DNA mutations - known as mutational signatures - which are essentially molecular imprints of past environmental exposures.
Combining these genomic data with estimates of air pollution (based on fine particle measurements by satellite and on the ground), they discovered that non-smokers living in more polluted environments had a significantly higher number of mutations in their lung tumors. For example, these individuals had 3.9 times more mutations related to smoking and a 76% increase in mutations related to aging.
This does not mean that pollution causes a unique "pollution mutational signature" per se, but it increases the total number of mutations, explains Díaz-Gay, a former postdoctoral researcher in Alexandrov's lab, who adds that "we see that air pollution is associated with an increase in somatic mutations, including those corresponding to known mutational signatures attributed to smoking and aging."
The researchers also observed that the more exposed a person was to pollution, the more mutations were present in their lung cancer. They also had shorter telomeres, a sign of accelerated cellular aging.
In addition to air pollution, another environmental risk has been identified: aristolochic acid, a carcinogen present in certain traditional medicinal herbs. A specific mutational signature linked to aristolochic acid was found almost exclusively in cases of lung cancer in Taiwanese individuals who had never smoked. Although aristolochic acid has been previously associated with bladder, gastrointestinal, renal, and liver cancers through ingestion, this is the first study providing evidence that it may contribute to lung cancer.
Furthermore, a new mutational signature was identified in a higher proportion in lung cancers of non-smokers compared to smokers. Its cause is unknown: it does not correlate with air pollution or any other known environmental exposure. "We observed it in most cases in this study, but we still do not know what causes it," says Alexandrov. "This is something completely different and opens up a completely new area of research," he emphasizes.
Analysis of other potential risks
In the future, researchers are expanding their study to include cases of lung cancer in non-smokers from Latin America, the Middle East, and more regions of Africa. The researchers are also focusing on other potential risks. One of them is marijuana consumption and e-cigarettes, especially among young people who have never smoked tobacco. The new CNIO group will also study other environmental risks, such as radon and asbestos, in collaboration with other groups in Spain. Additionally, they will gather more detailed data on local and individual-scale pollution.