Abstract LB231: The mutagenic forces shaping the genomic landscape of lung cancer in never smokers

Abstract While most lung cancers are associated with tobacco smoking, prior studies have indicated that 15-20% of cases are found in never smokers. Lung cancer in never smokers (LCINS) shows demographic variations, being more common in females and Asian populations. Epidemiological studies have also identified environmental risk factors for LCINS, including exposure to secondhand tobacco smoke and air pollution. As part of the Sherlock-Lung project (current data freeze of 1217 samples), we generated deep WGS data from a large international cohort of 871 treatment-naïve LCINS recruited from 28 locations across four continents. Our cohort allowed mapping the genomic landscape operative in lung cancer histologies commonly found in never smokers, including adenocarcinomas (n=737) and carcinoids (n=61), as well as other histologies rarely attributed to never smokers (n=73). Information on passive smoking was collected for 458 patients, with 250 being exposed to secondhand smoke. We identified driver alterations and performed mutational signature analyses for single base substitutions (SBS), indels, doublet base substitutions (DBS), copy number alterations, and structural variants. We detected eighteen SBS signatures, with eight not previously linked to LCINS, including SBS4, associated with smoking but also observed in lifelong non-smokers exposed to different environmental mutagens, such as indoor pollution. Several additional signatures were detected in other variant types, including a novel indel signature. Notably, secondhand smoke exposure corresponded to increased SBS burden, although it was not associated with specific signatures. In contrast, we observed a signature-specific association of air pollution (measured as PM2. 5 exposure) with SBS, indel, and DBS burden. SBS4 and correlated signatures ID3 and DBS2 were positively associated with PM2. 5 exposure. Similarly, clock-like signature SBS5 was highly correlated with PM2. 5, potentially acting as a readout of a promotion mechanism where lung cells undergo more cell divisions in individuals living in highly polluted areas. We also observed variability across histologies and ancestries for signatures and driver mutations, including enrichment of signatures SBS17b and SBS40a as well as KRAS mutations in adenocarcinomas from Europeans; aristolochic-acid associated signature SBS22a, and EGFR and TP53 mutations in adenocarcinomas from East Asians; and signature SBS8 and ARID1A mutations in carcinoids from Europeans. The unprecedented size of our cohort allowed us to refine the prevalence and intensity of the driver mutations and mutational signatures involved in LCINS, as well as their variability across ancestries, geographical locations, and histologies. Our results indicate that air pollution may act as both initiator and promoter of neoplastic expansion of LCINS. Citation Format: Marcos Diaz-Gay, Tongwu Zhang, Azhar Khandekar, Burçak Otlu, Shuvro Nandi, Christopher D. Steele, Nathaniel Rothman, Stephen J. Chanock, Qing Lan, Ludmil B. Alexandrov, Maria Teresa Landi. The mutagenic forces shaping the genomic landscape of lung cancer in never smokers abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB231.