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.
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