Lung Cancer in Never-Smokers: Mutational Processes Affect Genomic Landscape
Enriched mutations in never-smokers with lung cancer varied geographically, with EGFR and TP53 found in East Asian patients, and KRAS in those from North America and Europe.
Lung cancer in never-smokers (LCINS) living in areas with high air pollution is associated with a greater prevalence of TP53 mutations, shorter telomeres, and heightened mutagenesis, particularly associated with signatures SBS4 and SBS5. These were among study findings published in Nature.
Researchers assessed mutagenic exposures linked to lung cancer among never- smokers, identifying geographic and other differences in the mutational signatures and mutated cancer driver genes. International data from the Sherlock-Lung study was used to generate and analyze deep whole-genome sequencing (WGS) in treatment-naive never-smokers with lung cancer.
The Sherlock-Lung study enrolled 871 individuals from 28 locations in 4 continents (79% female). About 85% were diagnosed with adenocarcinomas (n=737). Data on passive smoking were available for 458 patients, of whom 250 were exposed and 208 were not exposed to secondhand tobacco smoke.
Considerable heterogeneity was observed for single base substitutions (SBSs) and copy-number alterations (CNs) in the genomic landscape of the 737 lung adenocarcinomas from never-smokers. About 4.9% of adenocarcinomas (36/737) had the tobacco-associated signature SBS4, with the most prevalent signature of SBS40a, with unknown etiology, which represented 28.2% of all substitutions.
Signature SBS22a was enriched among individuals from East Asia (odds ratio [OR], 21.3; 95% CI, 7.4-90.3). SBS22a was observed almost exclusively in individuals from Taiwan, along with the first evidence of aristolochic acid causing mutations in lung cancer.
EGFR and TP53 featured the most driver mutations (52.2% and 30.5%, respectively), mutated in adenocarcinomas, and KRAS was mutated in 6.5% of samples. EGFR and TP53 mutations were enriched in East Asian individuals, and KRAS mutations were enriched in North American and European individuals.
In a comparison of the LCINS cohort with 345 lung tumors from tobacco smokers, the expected enrichment of tobacco-associated signatures SBS4 and SBS100 in smokers was observed, and an increased prevalence of signature SBS40a occurred among never-smokers (OR, 5.5; 95% CI, 3.9-7.8). Signature SBS40a was the most differentially observed signature among never-smokers vs smokers.
The tobacco-associated signature SBS4 was active in 56 LCINS tumors (6.4%) and was the predominant signature in 39 (69.6%) and in many hypermutated cases (5.51-fold higher median SBS burden in SBS4+ cases).
An increase in SBS mutations was found in passive smokers, and a decrease was observed in the tumor-to-normal telomere length ratio. Of 250 cases exposed to secondhand smoke, 3 (1.2%) had signature SBS4 (Fisher’s exact test; OR, 0.62; 95% CI, 0.09-3.7; P =.71).
Patients living in areas with high PM2.5 levels had a greater burden of SBS, doublet base substitution, and indel mutations and with telomere shortening, after adjustment.
Several mutational signature-specific associations with individual PM2.5 estimates were observed after adjustment for covariates, including the clock-like signature SBS5. Individuals living in regions with increased PM2.5 exposure were 1.6 times more likely to have TP53 mutations (95% CI, 1.2-2.1) and 2.5 times less likely to have CTNNB1 mutations (95% CI, 1.3-4.7).
The researchers noted that analysis of the mutagenic role of outdoor air pollution was dependent on an average country-level and state- or province-level quantification of PM2.5,and exposure estimates were based on the area of residence at lung cancer diagnosis.
“[O]ur findings support the idea that exposure to aristolochic acid has a role in LCINS in Taiwanese individuals, suggest that passive smoking has low mutagenicity and implicate air pollution as both a mutagenic initiator and a potential promoter of neoplastic expansion — underscoring the importance of environmental mutagenic factors in shaping the lung cancer genomes of never smokers,” the investigators concluded.
Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Source: https://www.pulmonologyadvisor.com/news/lung-cancer-in-never-smokers-mutational-processes/