Context-dependent effects of CDKN2A and other 9p21 gene losses during the evolution of oesophageal cancer
Ganguli, P.; Colomina-Basanta, C.; Acha-Sagrado, A.; Misetic, H.; Armero-Pineiro, M.; Mendez, A.; Zahra, A.; Devonshire, G.; Kelly, G.; Freeman, A.; Green, M.; Nye, E.; Bichisecchi, A.; Bonfanti, P.; Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium, ; Rodriguez-Justo, M.; Spencer, J.; Fitzgerald, R. C.; Ciccarelli, F. D.
Show abstract
CDKN2A is a tumour suppressor located in chromosome 9p21 and frequently lost in Barretts oesophagus (BO) and oesophageal adenocarcinoma (OAC). How CDKN2A and other 9p21 gene co-deletions affect OAC evolution remains understudied. We explored the effects of 9p21 loss in OACs and cancer progressor and non-progressor BOs with matched genomic, transcriptomic, and clinical data. Despite its cancer driver role, CDKN2A loss in BO prevents OAC initiation by counter-selecting subsequent TP53 alterations. 9p21 gene co-deletions predict poor patient survival in OAC but not BO through context-dependent effects on cell cycle, oxidative phosphorylation, and interferon response. Immune quantifications using bulk transcriptome, RNAscope and high-dimensional tissue imaging showed that IFNE loss reduces immune infiltration in BO but not OAC. Mechanistically, CDKN2A loss suppresses the maintenance of squamous epithelium, contributing to a more aggressive phenotype. Our study demonstrates context-dependent roles of cancer genes during disease evolution, with consequences for cancer detection and patient management.
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