Abstract SS03-01: Unraveling the genetic and environmental risk factors for lung adenocarcinoma in Asia

Abstract In Asia, lung adenocarcinoma frequently occurs in never-smokers, and many of these tumors harbor EGFR mutations. This suggests that environmental and genetic factors promoting the development of lung cancer in never-smokers, or EGFR-mutant lung cancer, may be present in Asian populations. By performing whole-genome sequencing analyses of lung adenocarcinomas from never-smokers, passive smokers, and active smokers, we found that a substantial fraction of EGFR-positive lung adenocarcinomas arising in smokers lack the accumulation of SBS4 mutational signatures, representing so-called “molecular non-smokers.” In addition, passive smoking, a known risk factor for lung cancer in never-smokers, does not appear to be a risk factor for EGFR-mutant lung cancer (Mochizuki, JTO, 2024). These findings strongly suggest that factors other than smoking play a major role in the development of EGFR-mutant lung cancer. We have identified polymorphisms at the TERT and HLA class II loci as genetic factors that increase the risk of EGFR-mutant lung cancer. Based on these findings, we are currently investigating differences in the molecular properties of lung adenocarcinoma according to the distribution of these polymorphisms. In parallel, we are performing multi-omics analyses of early lung lesions in never-smokers, including adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA), with the aim of elucidating the mechanisms underlying the development of lung adenocarcinoma in never-smokers. Citation Format: Takashi Kohno. Unraveling the genetic and environmental risk factors for lung adenocarcinoma in Asia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr SS03-01.