Abstract 1748: Dearth of smoking-induced mutations in oncogene-driven NSCLCs despite smoking exposure

Abstract Non-small cell lung cancers (NSCLCs) in non-smokers are mostly driven by mutations in the oncogenes EGFR, ERBB2, and MET, and fusions involving ALK and RET. We term these “non-smoking-related oncogenes” (NSROs). NSRO-driven tumors account for approximately half of NSCLCs in East Asia, and, alarmingly, their age-adjusted incidence is increasing for unknown reasons. In addition to occurring in non-smokers, NSRO-driven tumors also occur in smokers. However, the clonal architecture and genomic landscape of these tumors remain largely unexplored. Here, we investigated genomic and transcriptomic alterations in 173 tumor sectors from 48 patients with NSRO-driven or typical-smoking NSCLCs. Overall, NSRO-driven NSCLCs in smokers and non-smokers had similar genomic landscapes and clonal architectures that were distinct from those in typical-smoking NSCLCs. Surprisingly, even in patients with prominent smoking histories, the mutational signature caused by tobacco smoking was essentially absent in NSRO-driven NSCLCs. We confirmed this unexpected finding in two large NSCLC data sets from other geographic regions. However, we observed differences in the tumor transcriptomes of NSRO-driven NSCLCs in smokers and non-smokers, with tumors in smokers displaying higher transcriptomic activities related to regulation of the cell cycle. This suggested that smoking does have an impact on tumor phenotype in NSCRO-driven NSCLC, likely through non-genetic mechanisms. We concluded that NSRO-driven NSCLCs, whether in non-smokers or smokers, constitute an important disease entity that is very different from typical-smoking NSCLC. Citation Format: Chen-Yang Huang, Nanhai Jiang, Meixin Shen, Gillianne Lai, Aaron C. Tan, Amit Jain, Stephanie P. Saw, Mei-Kim Ang, Quan Sing Ng, Darren Wan-Teck Lim, Ravindran Kanesvaran, Eng-Huat Tan, Wan Ling Tan, Boon-Hean Ong, Kevin L. Chua, Devanand Anantham, Angela Takano, Tony KH Lim, Wai Leong Tam, Ngak Leng Sim, Anders J. Skanderup, Daniel S.W. Tan, Steven G. Rozen. Dearth of smoking-induced mutations in oncogene-driven NSCLCs despite smoking exposure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1748.