Abstract 1746: KRAS mutant lung adenocarcinoma is associated with distinct mutational signature profiles
Authors: Woodhouse Laura , Hawari Aliah , Gruber Andreas , Lindsay Colin , Wedge David 
Published: March 2024

Background: Lung cancer is the 3rd most common cancer in the UK and 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 highlight potential therapeutic targets. This is the largest study to date to profile KRAS mutant LUAD mutational signatures using whole genome sequencing (WGS) data.

Methods: Paired tumor and germline WGS data were obtained through the 100 000 Genomes Project (Genomics England). KRAS mutations were profiled using Ensembl Variant Effect Predictor (VEP) v109.0. Single base substitution (SBS), doublet base substitution (DBS), small insertion and deletions (ID) and copy number (CN) mutational signature extraction was performed using SigProfiler (COSMIC version 3.3). Statistical analysis and plotting were performed in R; a two-tailed p-value &lt;0.05 was considered statistically significant.

Results: 680 LUAD patients were included; 301 KRAS mutant (44%), 379 KRAS wild type (63%). Common KRAS variants were present, including G12C (38.9%), G12V (15.9%) and G12D (14.0%). 17 SBS, 9 DBS, 10 ID and 9 CN signatures were extracted and present in both KRAS mutant and wild type cohorts. KRAS mutant samples were enriched in smoking related signatures (SBS4, DBS2, ID3; odds (OR) ratio 5.54, 3.80, 4.97 respectively, p &lt;0.001) and diploid CN signature (CN1, OR 1.41, p = 0.03). Conversely, KRAS mutant samples were less likely to have clocklike (ID5, OR 0.61, p = 0.012; ID8, OR 0.44, p &lt;0.001), APOBEC (SBS2, OR 0.49, p &lt;0.001; SBS13; 0.50, p &lt;0.001), chromosomal instability (CN9, OR 0.63, p = 0.019), loss of heterozygosity (CN14, OR 0.47, p = 0.015), or homologous recombination deficiency (CN17, OR 0.58, p &lt;0.001) signatures.

Discussion: These results show distinct mutational signature profiles between KRAS mutant and wild type LUAD. As previously described, KRAS mutant LUAD is dominated by smoking related signatures; however, the majority of remaining signatures were more common in the KRAS wild type cohort where there was a statistically significant difference. This data suggests different mutational processes are observed in KRAS mutant compared to wild type LUAD. KRAS mutations are commonly clonal and thought to initiate tumorigenesis: timing signatures relative to KRAS mutations is necessary to further our understanding of KRAS cancer evolution and the subject of future work. Combined with clinical data integration, mutational signatures could provide prognostic information and inform predictive models.

Citation Format: Laura Woodhouse, Aliah Hawari, Andreas Gruber, Colin Lindsay, David Wedge. KRAS mutant lung adenocarcinoma is associated with distinct mutational signature profiles [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 1746.