While scientists are still far from understanding the root causes behind most cancers, there are instances in which particular human behaviors have been linked to the development of specific cancers—one salient example is the link between cigarette smoking and lung cancer. This link, however, hides an uncomfortable truth: while those who smoke are likely to develop lung cancer, not everyone who gets lung cancer smokes! In fact, the incidence of lung cancer in never-smokers is higher than you might expect—up to 17% of men and 24% of women with lung cancer have no history of smoking, defined as a lifetime consumption of fewer than 100 cigarettes. As Dr. Sitapriya Moorthi, a former postdoctoral researcher in the Berger Lab at Fred Hutch, puts it, “When we consider lung cancer in never-smokers, we’re not talking about a tiny fraction of cases—if we considered lung cancer in never-smokers as its own disease, it would be the seventh-largest cause of cancer-related death globally!”
On a biological level, is lung cancer in never-smokers distinct from lung cancer in smokers? And why does lung cancer in never-smokers appear to be so prevalent in older women? Moorthi and Dr. Alice Berger addressed these questions in their recent study, published in the Journal of Clinical Investigation Insight. Working with collaborators at the Women’s Health Initiative (led by Dr. Garnet Anderson of the Public Health Sciences Division at Fred Hutch), they took advantage of a rich dataset which recorded clinical information and samples from over 160,000 women across the country, some of whom went on to develop lung cancer. For their study, they zeroed in on a group of ~70 post-menopausal women older than 50, most of whom were classified as ‘never-smokers.’ Then, they obtained tumor and normal tissue from these patients and performed custom whole exome sequencing (WES), which targets coding regions of the genome as well as regions known to have genomic translocations significant to lung cancer.
What did they find in these genome sequences? “Right off the bat, we were reassured to find trends in tumor mutational burden and specific oncogenic mutations between smokers and never-smokers that had previously been reported in other cohorts,” notes Moorthi. Indeed, they found a significantly higher tumor mutational burden in smokers compared to never-smokers, and they also noted trends in mutations in the notorious oncogenes KRAS and EGFR—tumors from smokers had significantly more mutations in KRAS, while tumors from never-smokers had significantly more EGFR mutations, particularly mutation types known as ‘insertions’ and ‘deletions.’ But Moorthi and team also found something which hadn’t been shown before: mutations in MGA, a tumor suppressor and member of the MYC transcription factor network (for more info, see here) were exclusively present in tumors from smokers. Cross-referencing their results with several larger-scale lung cancer genomics datasets confirmed that MGA mutations appear more frequently in smokers’ lung tumors than in never-smokers.
Equally as interesting as what Moorthi and Berger found was what they didn’t find. For example, when the team looked for mutational signatures (patterns that distinguish mutations arising from specific mutagens, like cigarette smoke), they noted that tumors from never-smokers showed little if any evidence of smoke exposure-associated mutational signatures, despite the fact that these patients still reported some ‘passive exposure’ to cigarette smoke. These findings support the notion that lung cancer in never-smokers is truly distinct from that of smokers, not simply a result of smoke exposure via means other than cigarettes.
When they turned their attention away from specific mutations and to larger-scale genomic alterations—including loss or duplication of whole genes, genomic regions, or even entire genomes—they found considerable diversity among tumors, but not in a way that systematically differed between smokers and never-smokers. “While other studies have used patterns of larger scale genomic lesions like chromosome arm copy number variants to group lung tumors from never-smokers, we find similar levels of variation in smokers’ tumors, suggesting that the processes that generate these lesions are characteristic of lung cancers in general and not related to smoking,” notes Moorthi.
Why should we care about studying all of these different mutations in smokers and never-smokers? “On the most basic level, looking at mutations can give us clues about the processes that contribute to tumorigenesis in each case,” notes Dr. Berger, “but also, mutations can determine the compatibility or effectiveness of specific therapies.” Moorthi agrees. “When we were looking at KRAS mutations, for example, we noticed that the G12C variant is significantly enriched in smokers compared to never-smokers—the few never-smokers who had mutations in KRAS instead preferentially showed the G12D variant. As G12C is currently the only druggable KRAS variant, it becomes important to understand the nuance in the way that KRAS is mutated in lung cancers from these two populations of patients.” Overall, while the team is still actively pursuing clues which explain why lung cancer in never-smokers seems to preferentially target women, they are excited to continue leveraging opportunities to collaborate with organizations like the Women’s Health Initiative to continue studying lung cancer in patient populations that all too often fly under the radar.
The spotlighted work was funded by the National Institutes of Health, the International Association for the Study of Lung Cancer, the Lung Cancer Foundation of America, the Prevent Cancer Foundation, the Seattle Translational Tumor Research Lung Cancer Program, and a Fred Hutch Translational Data Science Postdoctoral Fellowship, with support from the Genomics and Bioinformatics Shared Resource at Fred Hutch.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium members Drs. Alice Berger, Garnet Anderson, and Gavin Ha contributed to this study.
For a video abstract summarizing the findings of this study, see here.
Moorthi, S., Paguirigan, A., Itagi, P., Ko, M., Pettinger, M., Hoge, A. C. H., Nag, A., Patel, N. A., Wu, F., Sather, C., Levine, K. M., Fitzgibbon, M. P., Thorner, A. R., Anderson, G. L., Ha, G., & Berger, A. H. (2024). The genomic landscape of lung cancer in never-smokers from the Women’s Health Initiative. JCI Insight, 9(17), e174643.
Science Spotlight writer David Sokolov is a graduate student in the Sullivan Lab at the Fred Hutch. He studies how cancer cells modify their metabolism to facilitate rapid proliferation and accommodate tumor-driving mitochondrial defects. He's originally from the east coast and has bachelors' and masters' degrees from West Virginia University. Outside of the lab, you'll find him enjoying the outdoors, playing music, or raising composting worms in his front yard.
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