RT Journal Article
SR Electronic
T1 Mapping of Kras mutations during chemical carcinogenesis
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP PA660
DO 10.1183/13993003.congress-2021.PA660
VO 58
IS suppl 65
A1 Sabine J. Behrend
A1 Magda Spella
A1 Mario A. A. Pepe
A1 Georgia A. Giotopoulou
A1 Marina Lianou
A1 Ioanna Giopanou
A1 Anne-Sophie Lamort
A1 Georgios T. Stathopoulos
YR 2021
UL http://erj.ersjournals.com/content/58/suppl_65/PA660.abstract
AB Background: The tobacco carcinogen urethane causes lung adenocarcinomas (LUAD) in mice. They show high similarity to human LUAD of smokers, including driver KrasQ61R mutations. However, the timeline of KRASQ61R mutation acquisition and the affected cell lineages are still obscure.Objective: With this study we aim to identify which cells of the lung gain KrasQ61R mutations and when they occur in response to urethane treatment.Methods: Airway and alveolar GFP-lineage-marked mice received single urethane hits. Lungs were harvested at 0, 1, 2, 4, and 8 weeks and LUAD tumors were collected at 16, 24, and 32 weeks post-urethane. The DNA was subjected to digital droplet PCR interrogating the coexistence of GFP and KrasQ61R in the same DNA copy. RNA of tumors was submitted to sequencing for gene expression analysis.Results: Starting from even 1 week post-urethane, both airway and alveolar lineages suffered KrasQ61R mutations. In airway-labelled cells KrasQ61R mutations increased by 4.06% and 2.55% at 4 and 32 weeks post-urethane, respectively. In contrast, in alveolar-labelled cells KrasQ61R mutations declined by 5.92% and 6.12%. Strikingly, gene expression analysis on tumors revealed an over expression of alveolar markers whereas expression of airway marker genes decreased.Conclusion: After pulmonary tumor initiation by urethane, airway cells accumulate KrasQ61R mutations over time, whereas alveolar cells tend to lose them. However, tumor cells are over expressing alveolar cell markers and lose airway markers. Altogether, these results indicate that smoking-induced LUAD develops from club cells which acquire alveolar cell characteristics. These data provide further insights into the mechanisms underlying LUAD evolution in patients.FootnotesCite this article as: European Respiratory Journal 2021; 58: Suppl. 65, PA660.This abstract was presented at the 2021 ERS International Congress, in session “Prediction of exacerbations in patients with COPD”.This is an ERS International Congress abstract. No full-text version is available. Further material to accompany this abstract may be available at www.ers-education.org (ERS member access only).