Abstract 5657: The intricate relationship between genomic damage and epidemiological lung cancer risk in ever-smokers

Abstract Extensive epidemiological studies have illuminated the intricate relationship between tobacco smoking and lung cancer. Squamous cell carcinoma (LUSC), which is clinically tied to smoking, is formed in the proximal airway of the lung, whereas adenocarcinoma (LUAD), arising in the distal airway, has a weaker connection to tobacco and often occurs in never-smokers. The cessation of smoking promotes lung health and gradually lowers cancer risk. Dissecting the impact of smoking cessation on different lung cancer types in 650, 000 individuals from UK Biobank and PLCO, we confirmed previous findings of LUSC risk diminishing more rapidly after quitting smoking, while LUAD risk endures over time. We previously found that normal bronchial epithelium in the proximal airway accumulates DNA damage proportionally to an individual’s smoking habits. However, our analysis identified a population of cells with near-normal mutation burden, evading tobacco-induced damage. We hypothesized that the reduction in LUSC risk with smoking cessation could be explained by the repopulation of the proximal airway by these cells. Here, we followed up on this finding by exploring the genomics of alveolar stem cells (ASCs), which are believed to be the origin of LUAD. Analyzing WGS data of 800 single-cell-derived organoids from 9 patients, we found that tobacco smoking is the major driver of increased mutation burden in ever- compared to never-smokers. More importantly, our results demonstrated no significant difference in the burden of tobacco-induced genomic damage between ex- and current-smokers, suggesting that DNA damage in the distal airway is both persistent and long-lasting. Using single-molecule sequencing in a cohort of 43 individuals with heterogeneous smoking histories confirmed this observation. Overall, contrasting this finding with the results from bronchial epithelium and the epidemiological lung cancer risk brings forth a genomic explanation for the differences in long-term cancer risk, ingrained in the abundance of near-normal mutation burden cells. By contextualizing our results within the carcinogenic process in the lung, we suggest that persistent genomic alterations are the major driver in the long-standing discussion about the reason for an epidemiological shift from LUSC to LUAD in the last 30 years. As the largest proportion of lung cancers occurs within ex-smokers, the persistent genomic damage in the distal airway will result in a relative increase in LUAD incidence compared to LUSC, likely explaining this clinical phenomenon. Citation Format: Moritz Jakob Przybilla, Amany Ammar, Hugh Selway-Clarke, Andrew R. Lawson, Hyunchul Jung, Adam Pennycuick, Kate Gowers, Ryan C. Khaw, Zoe Frazer, Kate Davies, Inigo Martincorena, Sam Janes, Peter J. Campbell. The intricate relationship between genomic damage and epidemiological lung cancer risk in ever-smokers 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 (6Suppl): Abstract nr 5657.