Tobacco smoke alters the landscape of mutation, selection, and epistasis in lung adenocarcinoma

The mutagenic effects of tobacco smoke are well-reported. However, tobacco smoke also likely alters the somatic selective pressures that drive lung cancer evolution, and these altered pressures have never been quantified nor compared to the oncogenic effects of tobacco-induced mutagenesis. This comparison is necessary for prediction of targeted therapy efficacy given exposure history. Here, we estimated background mutation rates, somatic selection, and selective epistasis for 21 driver genes in ever- and never-smoker lung adenocarcinoma (ES-and NS-LUAD). As expected, mutation rates were gene-specifically elevated in ES-LUAD. However, variant prevalence differences between ES- and NS-LUAD could not be explained by differential mutagenesis. KRAS, KEAP1, and STK11 mutations were more strongly selected in ES-LUAD. EGFR, PIK3CA, and SMAD4 mutations were more strongly selected in NS-LUAD, wherein EGFR mutations were associated with upregulation of epithelial-mesenchymal transition--a functional consequence specific to exposure history. Epistasis was pervasive and context-dependent: ES-LUAD exhibited more synergy and less antagonism, implying a broader, more navigable adaptive landscape than NS-LUAD. We also performed the first systematic quantification of higher-order-than-pairwise epistasis, revealing sub-additive and emergent synergies that shape cancer evolution. Our results disambiguate the mutagenic and selective effects of tobacco smoke, demonstrating how environmental insults reshape cancer evolution and enabling prediction of therapeutic efficacy based on smoking history and somatic genotype. Author SummarySmoking is a well-known cause of lung cancer because it increases the number of mutations in lung cells. But tobacco smoke also causes inflammation and other physiological changes that might influence how tumors evolve. Using DNA from lung tumors, we asked whether these changes make certain mutations more helpful to cancer growth and thereby better targets for therapy. We also asked whether some mutations were more helpful to cancer growth in those who havent smoked. To do so, we estimated not only how often mutations occurred, but also how strongly they were favored during cancer development. Focusing on 21 key lung cancer genes, including KRAS, EGFR, and TP53, we found that mutations in some, such as KRAS and KEAP1 were more strongly favored in smokers. Mutations in genes such as EGFR and PIK3CA were more strongly favored in non-smokers, where they were also linked to non-smoker-specific changes in gene activity. We also found that mutations in tumors interact differently depending on smoking history: smokers tumors showed more cooperation between mutations, which may help them evolve in more flexible ways. This study shows how smoking reshapes the genetic paths lung cancers take--and why a patients smoking history matters when choosing targeted treatments. Understanding these evolutionary patterns can help improve treatment decisions and lead to more personalized care for lung cancer patients.