Non–small cell lung cancers (NSCLC) in nonsmokers are mostly driven by mutations in the oncogenes EGFR, ERBB2, and MET and fusions involving ALK and RET. In addition to occurring in nonsmokers, alterations in these “nonsmoking-related oncogenes” (NSRO) also occur in smokers. To better understand the clonal architecture and genomic landscape of NSRO-driven tumors in smokers compared with typical-smoking NSCLCs, we investigated genomic and transcriptomic alterations in 173 tumor sectors from 48 NSCLC patients. NSRO-driven NSCLCs in smokers and nonsmokers had similar genomic landscapes. Surprisingly, even in patients with prominent smoking histories, the mutational signature caused by tobacco smoking was essentially absent in NSRO-driven NSCLCs, which was confirmed in two large NSCLC data sets from other geographic regions. However, NSRO-driven NSCLCs in smokers had higher transcriptomic activities related to the regulation of the cell cycle. These findings suggest that, whereas the genomic landscape is similar between NSRO-driven NSCLC in smokers and nonsmokers, smoking still affects the tumor phenotype independently of genomic alterations.


Non-small cell lung cancers driven by nonsmoking-related oncogenes do not harbor genomic scars caused by smoking regardless of smoking history, indicating that the impact of smoking on these tumors is mainly nongenomic.

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