Abstract
Background: KRAS mutations are frequent in lung adenocarcinoma (LADC). Despite intensive research, KRAS mutations cannot be targeted, possibly due to their addiction with other, yet unidentified oncogenes.
Objectives: To identify potential addiction partners of KRAS using mouse models of tobacco chemical-induced LADC.
Methods: We used urethane and diethylnitrosamine, tobacco carcinogens(TC), to induce LADC in different strains of inbred mice and established cell lines thereof(n = 13). Cellular RNA was subjected to next generation sequencing using the IonTorrent platform. Data were analysed for transcript abundance and sequence alignment, pathways and gene set enrichment, and analyzed single nucleotide variation(SNV) effect on the protein three dimensional structure(3DS) and their interaction
Results: We detected 638 genes differentially expressed(Z score>|2|) in LADC cells compared with primary lung epithelial cells. Among those, we found altered elements of trascription, G2/S progression and DNA replication pathways. In 46,866 SNV identified specifically across LADC cell lines, we identified 15 common SNV, in addition to mutant KRAS in codon 61. Among these candidate KRAS addiction partners, we pinned genes important in cell cycle, trascription and protein degradation. Moreover, those SNV altered 3DS of proteins involved in important metabolic process and cancer progression.
Conclusion: A TC that causes KRAS mutation, also causes changes in gene expression and 15 mutation. Amazingly the same changes occur among 10 different cell lines induced with different carcinogens and in different mouse strain. We believe that important partners in crime of KRAS lie among those genes
Footnotes
Cite this article as: European Respiratory Journal 2018 52: Suppl. 62, PA2841.
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).
- Copyright ©the authors 2018