A brand new examine reveals that air air pollution, conventional natural medicines and different environmental exposures are linked to genetic mutations which will contribute to the event of lung most cancers in folks with no or hardly any historical past of smoking.
Lung most cancers has lengthy been considered a smoker’s illness. However as tobacco use has declined in lots of components of the world, a troubling development has emerged: lung most cancers in individuals who have by no means smoked is proportionally on the rise. Furthermore, this type of most cancers disproportionately impacts girls, significantly these of Asian ancestry, and tends to be extra prevalent in East Asian than in Western nations.
Now, a examine printed in Nature has uncovered compelling genomic proof that factors to air air pollution—and different environmental exposures—as a possible main issue behind this rising public well being concern.
The examine was collectively led by researchers on the College of California San Diego and the Nationwide Most cancers Institute (NCI), a part of the Nationwide Institutes of Well being (NIH).
“We’re seeing this problematic development that never-smokers are more and more getting lung most cancers, however we’ve not understood why,” mentioned examine co-senior writer Ludmil Alexandrov, professor of bioengineering and mobile and molecular medication at UC San Diego, and member of UC San Diego Moores Most cancers Middle.
“Our analysis exhibits that air air pollution is strongly related to the identical forms of DNA mutations we usually affiliate with smoking.”
“That is an pressing and rising international downside that we’re working to grasp concerning never-smokers,” mentioned Maria Teresa Landi, epidemiologist within the Division of Most cancers Epidemiology and Genetics on the NCI and co-senior writer of the examine.
“Most earlier lung most cancers research haven’t separated knowledge of people who smoke from non-smokers, which has restricted insights into potential causes in these sufferers. Now we have designed a examine to gather knowledge from never-smokers around the globe and use genomics to hint again what exposures could be inflicting these cancers.”
And whereas earlier research within the literature have proven an epidemiological hyperlink between air air pollution and lung most cancers in never-smokers, this new analysis goes additional by displaying a genomic hyperlink.
Mutational results of air air pollution
The staff analyzed lung tumors from 871 never-smokers residing in 28 areas with completely different ranges of air air pollution throughout Africa, Asia, Europe and North America. Utilizing whole-genome sequencing, the researchers recognized distinct patterns of DNA mutations—often called mutational signatures—that act like molecular fingerprints of previous exposures.
By combining these genomic knowledge with air pollution estimates primarily based on satellite tv for pc and ground-level measurements of effective particulate matter, the researchers have been capable of estimate people’ long-term publicity to air air pollution.
They discovered that never-smokers residing in additional polluted environments had considerably extra mutations of their lung tumors, significantly driver mutations—which immediately promote most cancers growth—and mutational signatures linked to most cancers—which function a report of all previous mutagenic exposures. For instance, these people had a 3.9-fold enhance in a mutational signature linked to tobacco smoking and a 76% enhance in one other signature linked to getting old.
This does not imply that air pollution causes a singular “air air pollution mutational signature” per se, famous examine co-first writer Marcos Díaz-Homosexual, a former postdoctoral researcher in Alexandrov’s lab who’s now a junior group chief on the Spanish Nationwide Most cancers Analysis Middle (CNIO) in Madrid, Spain. Somewhat, it will increase the general variety of mutations, significantly in identified pathways of DNA harm.
“What we see is that air air pollution is related to a rise in somatic mutations, together with people who fall below identified mutational signatures attributed to tobacco smoking and getting old,” mentioned Díaz-Homosexual.
The researchers additionally famous a dose-response relationship: the extra air pollution somebody was uncovered to, the extra mutations have been discovered of their lung tumors. These tumors additionally had shorter telomeres—the protecting caps on the ends of chromosomes—which is an indication of accelerated mobile getting old.
Shocking discovering from secondhand smoke publicity
In distinction, the researchers didn’t discover a robust genetic correlation with secondhand smoke. Lung tumors of never-smokers uncovered to secondhand smoke confirmed solely a slight enhance in mutations, together with shorter telomeres, however no distinct mutational signatures or driver mutations. Whereas publicity to secondhand smoke is a identified most cancers danger, its mutational impact was far much less pronounced than that seen with air air pollution.
“If there’s a mutagenic impact of secondhand smoke, it could be too weak for our present instruments to detect,” mentioned examine co-first writer Tongwu Zhang, an Earl Stadtman Investigator within the Biostatistics Department of the NCI. “Nonetheless, its organic results are nonetheless evident within the important telomere shortening.”
The researchers acknowledged that their evaluation may very well be additional restricted by the complexity of measuring secondhand smoke publicity. “It is tough to get that type of info as a result of it relies on varied components, such because the period of time one was uncovered; how far one was from publicity; and the way typically one shared an area with another person who smoked, for instance,” mentioned Díaz-Homosexual.
Danger discovered from natural medication
Along with air air pollution, researchers recognized one other environmental danger: aristolochic acid, a carcinogen present in sure conventional Chinese language natural medicines. A selected mutational signature linked to aristolochic acid was discovered virtually completely in lung most cancers instances of never-smokers from Taiwan.
Although aristolochic acid has beforehand been linked to bladder, gastrointestinal, kidney and liver cancers from ingestion, that is the primary examine to report proof that it could contribute to lung most cancers. The researchers suspect that these instances could come up from inhalation of conventional Chinese language natural medicines, however extra knowledge are wanted to assist their speculation.
“This raises new considerations about how conventional cures may unintentionally increase most cancers danger,” mentioned Landi. “It additionally presents a public well being alternative for most cancers prevention—significantly in Asia.”
New signature, new questions
In one other intriguing discovery, the staff recognized a brand new mutational signature that seems within the lung cancers of most never-smokers however is absent in people who smoke. Its trigger stays unknown—it didn’t correlate with air air pollution or another identified environmental publicity.
“We see it within the majority of instances on this examine, however we do not but know what’s driving it,” mentioned Alexandrov. “That is one thing completely completely different, and it opens up a complete new space of investigation.”
Shifting ahead, the researchers are increasing their examine to incorporate lung most cancers instances of never-smokers from Latin America, the Center East and extra areas of Africa. The researchers are additionally turning their consideration to different potential dangers. One focus is on marijuana and e-cigarette use, significantly amongst youthful individuals who have by no means smoked tobacco.
The staff is investigating whether or not these exposures might also contribute to mutational modifications in lung tissue. In addition they goal to check different environmental dangers—comparable to radon and asbestos—in addition to collect extra detailed air pollution knowledge at native and particular person ranges.
Extra info:
Maria Teresa Landi, The mutagenic forces shaping the genomes of lung most cancers in never-smokers, Nature (2025). DOI: 10.1038/s41586-025-09219-0. www.nature.com/articles/s41586-025-09219-0
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