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

Autor: Ganguli P; Cancer Systems Biology Laboratory, The Francis Crick Institute, London, UK.; Barts Cancer Institute - Centre for Cancer Evolution, Queen Mary University of London, London, UK., Basanta CC; Cancer Systems Biology Laboratory, The Francis Crick Institute, London, UK.; Barts Cancer Institute - Centre for Cancer Evolution, Queen Mary University of London, London, UK., Acha-Sagredo A; Cancer Systems Biology Laboratory, The Francis Crick Institute, London, UK.; Barts Cancer Institute - Centre for Cancer Evolution, Queen Mary University of London, London, UK., Misetic H; Cancer Systems Biology Laboratory, The Francis Crick Institute, London, UK.; Barts Cancer Institute - Centre for Cancer Evolution, Queen Mary University of London, London, UK., Armero M; Cancer Systems Biology Laboratory, The Francis Crick Institute, London, UK.; Barts Cancer Institute - Centre for Cancer Evolution, Queen Mary University of London, London, UK., Mendez A; Cancer Systems Biology Laboratory, The Francis Crick Institute, London, UK.; Barts Cancer Institute - Centre for Cancer Evolution, Queen Mary University of London, London, UK., Zahra A; Cancer Systems Biology Laboratory, The Francis Crick Institute, London, UK.; Barts Cancer Institute - Centre for Cancer Evolution, Queen Mary University of London, London, UK., Devonshire G; Early Cancer Institute, Hutchison Research Centre, University of Cambridge, Cambridge, UK., Kelly G; Bioinformatics & Biostatistics STP, The Francis Crick Institute, London, UK., Freeman A; Early Cancer Institute, Hutchison Research Centre, University of Cambridge, Cambridge, UK., Green M; Experimental Histopathology STP, The Francis Crick Institute, London, UK., Nye E; Experimental Histopathology STP, The Francis Crick Institute, London, UK., Bichisecchi A; Epithelial Stem Cell Biology & Regenerative Medicine Laboratory, The Francis Crick Institute, London, UK.; Institute of Immunity & Transplantation, Division of Infection & Immunity, UCL, London, UK., Bonfanti P; Epithelial Stem Cell Biology & Regenerative Medicine Laboratory, The Francis Crick Institute, London, UK.; Institute of Immunity & Transplantation, Division of Infection & Immunity, UCL, London, UK., Rodriguez-Justo M; Department of Pathology, UCL Cancer Institute, London, UK., Spencer J; School of Immunology and Microbial Sciences, King's College London, London, UK., Fitzgerald RC; Early Cancer Institute, Hutchison Research Centre, University of Cambridge, Cambridge, UK., Ciccarelli FD; Cancer Systems Biology Laboratory, The Francis Crick Institute, London, UK. f.ciccarelli@qmul.ac.uk.; Barts Cancer Institute - Centre for Cancer Evolution, Queen Mary University of London, London, UK. f.ciccarelli@qmul.ac.uk.
Jazyk: angličtina
Zdroj: Nature cancer [Nat Cancer] 2025 Jan 03. Date of Electronic Publication: 2025 Jan 03.
DOI: 10.1038/s43018-024-00876-0
Abstrakt: CDKN2A is a tumor suppressor located in chromosome 9p21 and frequently lost in Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). How CDKN2A and other 9p21 gene co-deletions affect EAC evolution remains understudied. We explored the effects of 9p21 loss in EACs and cancer progressor and non-progressor BEs with matched genomic, transcriptomic and clinical data. Despite its cancer driver role, CDKN2A loss in BE prevents EAC initiation by counterselecting subsequent TP53 alterations. 9p21 gene co-deletions predict poor patient survival in EAC but not BE 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 BE, but not EAC. 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 Interests: Competing interests: R.C.F. is named on patents related to Cytosponge and related assays which have been licensed by the Medical Research Council to Covidien GI Solutions (now Medtronic) and is a co-founder and shareholder (<3%) of CYTED Ltd. The Fitzgerald lab also has an ongoing collaboration with AstraZeneca. The other authors declare no competing interests.
(© 2025. The Author(s).)
Databáze: MEDLINE
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