Context-dependent effects of CDKN2A and other 9p21 gene losses during the evolution of oesophageal cancer

CDKN2A is a tumour suppressor gene located in chromosome 9p21 and frequently lost in Barrett's 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 pro...

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Published inbioRxiv
Main Authors Ganguli, Piyali, Colomina-Basanta, Celia, Mendez, Akram, Armero-Pineiro, Maria, Aeman Zahra, Acha-Sagrado, Amelia, Misetic, Hrvoje, Devonshire, Ginny, Kelly, Gavin, Freeman, Adam, Green, Mary, Nye, Emma, Oesophageal Cancer Clinical And Molecular Stratification (Occams) Consortium, Rodriguez-Justo, Manuel, Spencer, Jo, Fitzgerald, Rebecca C, Ciccarelli, Francesca D
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 26.01.2024
Subjects
Adenocarcinoma
Barrett's esophagus
Cancer
Cell cycle
Chromosome 9
Epithelium
Evolutionary genetics
Metastases
Oxidative phosphorylation
p53 Protein
Phenotypes
Phosphorylation
Transcriptomes
Transcriptomics
Tumor suppressor genes
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Summary:CDKN2A is a tumour suppressor gene located in chromosome 9p21 and frequently lost in Barrett's 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 counterselecting acquisition of 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.Competing Interest StatementThe authors have declared no competing interest.
DOI:10.1101/2024.01.24.576991