Abstract 6795: The Genomics England 100,000 genome programme: Allele-specific KRAS mutational signatures define distinct subtypes in lung adenocarcinoma

Abstract Background: Lung cancer is the leading cause of cancer mortality worldwide. Somatic RAS mutations are the most common oncogenes in human cancer, and KRAS mutations are the largest molecular subset of lung adenocarcinoma (LUAD). Each cancer genome accumulates a unique combination of somatic mutations, and these mutational signatures provide a genetic imprint of mutational processes that have occurred during tumorigenesis. Mutational signatures provide information on tumor aetiology/maintenance and could inform potential therapeutic targets or early detection strategies. Methods: Paired tumor and germline WGS data were obtained through the 100 000 Genomes Project (Genomics England). KRAS mutations were annotated using Ensembl Variant Effect Predictor (VEP) v109.0. Single base substitution (SBS), doublet base substitution (DBS), small insertion and deletions (ID), structural variant (SV) and copy number (CN) mutational signature extraction was performed using SigProfiler (COSMIC version 3.4). Survival analysis was performed using multivariate cox-proportional hazard models, adjusting for clinical stage and patient age at diagnosis. Statistical analyses and plotting were performed in R (version 4.2.1), with two-tailed p-values <0.05 considered statistically significant. Results: 680 LUAD patients were included; 301 KRAS mutant (44%) and 379 KRAS wild type (56%). 64 mutational signatures were extracted from the LUAD cohort, comprising 23 SBS, 10 DBS, 12 Indel, 9 CN and 10 SV signatures. Unsupervised clustering revealed three distinct mutational signature subsets, reflecting different mutagenic origins and biological pathways: a smoking-associated cluster (cluster 2), an APOBEC non-smoking-associated cluster (cluster 3) and a clock-like non-smoking-associated cluster (cluster 1). As anticipated, cluster 2 was strongly associated with KRAS mutation. However, KRAS allele-specific profiling revealed striking variation of smoking impact: G12C and G13C variants displayed strong tobacco-derived mutational signatures, including direct probabilistic associations inferred at the individual KRAS somatic variant level. G12D was more commonly associated with clock-like related mutational processes and RBM10 mutation. G12A was enriched for normal diploid segments (CN1). Finally, CN6, SV2 and SV9 signatures were independently associated with inferior overall survival in a KRAS-dependent context. Discussion: This is the largest study to date to profile KRAS mutant LUAD mutational signatures using whole genome sequencing (WGS) data. KRAS allele-specific profiling reveals distinct mutational and co-mutation contexts that define biologically and clinically meaningful subtype heterogeneity. Many KRAS-mutant subtypes in LUAD are not a direct consequence of smoking. Citation Format: Laura C. Woodhouse, Aliah Hawari, Avraam Tapinos, Andreas Gruber, Alex J. Cornish, Genomics England Research Consortium, David C. Wedge, Colin R. Lindsay. The Genomics England 100,000 genome programme: Allele-specific KRAS mutational signatures define distinct subtypes in lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6795.