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<p><i>CDKN2A</i> is a tumor suppressor located in chromosome 9p21 and frequently lost in Barrett’s esophagus (BE) and esophageal adenocarcinoma (EAC). How <i>CDKN2A</i> 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, <i>CDKN2A</i> loss in BE prevents EAC initiation by counterselecting subsequent <i>TP53</i> 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 <i>IFNE</i> loss reduces immune infiltration in BE, but not EAC. Mechanistically, <i>CDKN2A</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月3日

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  • Piyali Ganguli,
  • Celia C. Basanta,
  • Amelia Acha-Sagredo,
  • Hrvoje Misetic,
  • Maria Armero,
  • Akram Mendez,
  • Aeman Zahra,
  • Ginny Devonshire,
  • Gavin Kelly,
  • Adam Freeman,
  • Mary Green,
  • Emma Nye,
  • Anita Bichisecchi,
  • Paola Bonfanti,
  • Rebecca C. Fitzgerald,
  • Paul A. W. Edwards,
  • Nicola Grehan,
  • Barbara Nutzinger,
  • Aisling M. Redmond,
  • Christine Loreno,
  • Sujath Abbas,
  • Adam Freeman,
  • Elizabeth C. Smyth,
  • Maria O’Donovan,
  • Ahmad Miremadi,
  • Shalini Malhotra,
  • Monika Tripathi,
  • Hannah Coles,
  • Curtis Millington,
  • Matthew Eldridge,
  • Maria Secrier,
  • Ginny Devonshire,
  • Jim Davies,
  • Charles Crichton,
  • Nick Carroll,
  • Richard H. Hardwick,
  • Peter Safranek,
  • Andrew Hindmarsh,
  • Vijayendran Sujendran,
  • Stephen J. Hayes,
  • Yeng Ang,
  • Andrew Sharrocks,
  • Shaun R. Preston,
  • Izhar Bagwan,
  • Vicki Save,
  • Richard J. E. Skipworth,
  • Ted R. Hupp,
  • J. Robert O’Neill,
  • Olga Tucker,
  • Andrew Beggs,
  • Philippe Taniere,
  • Sonia Puig,
  • Gianmarco Contino,
  • Timothy J. Underwood,
  • Robert C. Walker,
  • Ben L. Grace,
  • Jesper Lagergren,
  • James Gossage,
  • Andrew Davies,
  • Fuju Chang,
  • Ula Mahadeva,
  • Vicky Goh,
  • Francesca D. Ciccarelli,
  • Grant Sanders,
  • Richard Berrisford,
  • David Chan,
  • Ed Cheong,
  • Bhaskar Kumar,
  • L. Sreedharan,
  • Simon L. Parsons,
  • Irshad Soomro,
  • Philip Kaye,
  • John Saunders,
  • Laurence Lovat,
  • Rehan Haidry,
  • Michael Scott,
  • Sharmila Sothi,
  • Suzy Lishman,
  • George B. Hanna,
  • Christopher J. Peters,
  • Krishna Moorthy,
  • Anna Grabowska,
  • Richard Turkington,
  • Damian McManus,
  • Helen Coleman,
  • Russell D. Petty,
  • Freddie Bartlett,
  • Manuel Rodriguez-Justo,
  • Jo Spencer,
  • Rebecca C. Fitzgerald,
  • Francesca D. Ciccarelli

摘要

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.