The mutagenic forces shaping the genomes of lung cancer in never smokers

M. Díaz-Gay

Lung cancer in never smokers (LCINS) accounts for around 25% of all lung tumors and has been associated with exposure to passive smoking and air pollution in observational studies. We used data from the Sherlock-Lung study to evaluate mutagenic exposures by examining the cancer genomes of 871 LCINS patients from 28 countries. We observed regional differences, with a higher prevalence of KRAS mutations in North Americans and Europeans, and of EGFR and TP53 mutations in East Asians. Exposure to passive smoking was not associated with individual driver mutations or mutational signatures. By contrast, patients from highly polluted regions showed shorter telomeres and increased mutagenesis, linked to TP53 mutations and specific signatures, including SBS4, previously linked to tobacco smoking. A positive dose–response effect was observed with air-pollution levels. Our results elucidate the diversity of mutational processes shaping the genomic landscape of lung cancer in never smokers.

Keywords: lung cancer in never smokers, cancer genomics, somatic mutations, air pollution, mutational signatures

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