Abstract LT05: How EGFR Mutations Shape Lung Cancer in Never-Smokers

Abstract Lung cancer is classically linked to tobacco, yet in East Asia, a striking proportion arises in never-smokers—accounting for up to 48% of cases in Singapore. Paradoxically, these lung cancers in never-smokers (LCINS), often driven by EGFR mutations, exhibit a lower tumour mutation burden than smoking-associated counterparts, yet remain highly aggressive. This is particularly relevant for Asian women, where EGFR mutations are found in over 70% of LCINS cases. To understand the oncogenic mechanisms in EGFR-mutant LCINS, we conducted the largest multi-region whole-exome and transcriptome sequencing study to date, spanning 578 tumour samples from 180 early-stage, treatment-naïve patients. Despite low point mutation rates, our findings revealed pervasive chromosomal instability and frequent clonal whole-genome doubling in EGFR-mutant LCINS. We observed recurrent arm-level amplifications of 1q, 5p, and 7p, suggesting a deterministic chromosomal evolution. Transcriptomic analysis further demonstrated that these amplified regions confer significant proliferative and survival advantages, identifying a key mechanism of EGFR-driven tumorigenesis in LCINS. Importantly, unsupervised clustering of EGFR-mutant LCINS cases identified four subtypes with distinct evolutionary trajectories: 1) “Mosaic”, characterized by genomic diploidy and high intra-tumour heterogeneity; 2) two chromosomally unstable subtypes, “Unstable” and “Doubler”, exhibiting increasing genomic chaos; and 3) a rare “Mutator” subtype, with high APOBEC activity and CD8+ T-cell infiltration. Together, our findings shed light on how EGFR mutations drive lung cancer in never-smokers and offer a framework for subtype-specific prognostication and therapeutic intervention in early-stage disease. Citation Format: Komal Gupta, Dawn Lau Pingxi, Kenneth Chow, Ngak Leng Sim, Mengyuan Pang, Stephanie P L Saw, Wanjin Hong, Anders Jacob Skanderup, Regina Hoo, Daniel Shao Weng Tan. How EGFR Mutations Shape Lung Cancer in Never-Smokers abstract. In: Proceedings of Frontiers in Cancer Science 2025; 2025 Nov 5-7; Singapore. Philadelphia (PA): AACR; Cancer Res 2026;86 (13Suppl): Abstract nr LT05.