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

Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium

doi:10.1038/s43018-024-00876-0

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

Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	English
Article number	35
Pages (from-to)	158-174
Number of pages	17
Journal	Nature Cancer
Volume	6
Issue number	1
DOIs	https://doi.org/10.1038/s43018-024-00876-0
Publication status	Published - 1 Jan 2025

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@article{58e5e117bc9a4edd85083c5b5195baf4,

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

abstract = "CDKN2A is a tumor suppressor located in chromosome 9p21 and frequently lost in Barrett{\textquoteright}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.",

author = "{Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium} and Piyali Ganguli and Basanta, {Celia C.} and Amelia Acha-Sagredo and Hrvoje Misetic and Maria Armero and Akram Mendez and Aeman Zahra and Ginny Devonshire and Gavin Kelly and Adam Freeman and Mary Green and Emma Nye and Anita Bichisecchi and Paola Bonfanti and Freddie Bartlett and Petty, {Russell D.} and Helen Coleman and Damian McManus and Richard Turkington and Anna Grabowska and Krishna Moorthy and Peters, {Christopher J.} and Hanna, {George B.} and Suzy Lishman and Sharmila Sothi and Michael Scott and Rehan Haidry and Laurence Lovat and John Saunders and Philip Kaye and Irshad Soomro and Parsons, {Simon L.} and L. Sreedharan and Bhaskar Kumar and Ed Cheong and David Chan and Richard Berrisford and Grant Sanders and Ciccarelli, {Francesca D.} and Vicky Goh and Ula Mahadeva and Fuju Chang and Andrew Davies and James Gossage and Jesper Lagergren and Grace, {Ben L.} and Walker, {Robert C.} and Underwood, {Timothy J.} and Gianmarco Contino and Ciccarelli, {Francesca D.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

month = jan,

day = "1",

doi = "10.1038/s43018-024-00876-0",

language = "English",

volume = "6",

pages = "158--174",

journal = "Nature Cancer",

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T1 - Context-dependent effects of CDKN2A and other 9p21 gene losses during the evolution of esophageal cancer

AU - Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium

AU - Ganguli, Piyali

AU - Basanta, Celia C.

AU - Acha-Sagredo, Amelia

AU - Misetic, Hrvoje

AU - Armero, Maria

AU - Mendez, Akram

AU - Zahra, Aeman

AU - Devonshire, Ginny

AU - Kelly, Gavin

AU - Freeman, Adam

AU - Green, Mary

AU - Nye, Emma

AU - Bichisecchi, Anita

AU - Bonfanti, Paola

AU - Bartlett, Freddie

AU - Petty, Russell D.

AU - Coleman, Helen

AU - McManus, Damian

AU - Turkington, Richard

AU - Grabowska, Anna

AU - Moorthy, Krishna

AU - Peters, Christopher J.

AU - Hanna, George B.

AU - Lishman, Suzy

AU - Sothi, Sharmila

AU - Scott, Michael

AU - Haidry, Rehan

AU - Lovat, Laurence

AU - Saunders, John

AU - Kaye, Philip

AU - Soomro, Irshad

AU - Parsons, Simon L.

AU - Sreedharan, L.

AU - Kumar, Bhaskar

AU - Cheong, Ed

AU - Chan, David

AU - Berrisford, Richard

AU - Sanders, Grant

AU - Ciccarelli, Francesca D.

AU - Goh, Vicky

AU - Mahadeva, Ula

AU - Chang, Fuju

AU - Davies, Andrew

AU - Gossage, James

AU - Lagergren, Jesper

AU - Grace, Ben L.

AU - Walker, Robert C.

AU - Underwood, Timothy J.

AU - Contino, Gianmarco

AU - Ciccarelli, Francesca D.

PY - 2025/1/1

Y1 - 2025/1/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s43018-024-00876-0

DO - 10.1038/s43018-024-00876-0

M3 - Article

C2 - 39753721

AN - SCOPUS:85213940578

SN - 2662-1347

VL - 6

SP - 158

EP - 174

JO - Nature Cancer

JF - Nature Cancer

IS - 1

M1 - 35

ER -

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

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