Context-dependent effects of CDKN2A and other 9p21 gene losses during the evolution of esophageal cancer
Piyali Ganguli, Celia De Los Angeles Colomina Basanta, Amelia Acha‐Sagredo, Hrvoje Mišetić, María Armero, Akram Mendez, Aeman Zahra, Ginny Devonshire, Gavin Kelly, Adam Freeman, Mary Green, Emma Nye, Anita Bichisecchi, Paola Bonfanti, Rebecca C. Fitzgerald, Paul A. Edwards, Nicola Grehan, Barbara Nutzinger, Aisling M. Redmond, Christine Loreno, Sujath Abbas, Adam Freeman, Elizabeth 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 Hardwick, Peter Safranek, Andrew Hindmarsh, Vijayendran Sujendran, Stephen J. Hayes, Yeng Ang, Andrew D Sharrocks, Shaun R. Preston, Izhar Bagwan, Vicki Save, Richard J.E. Skipworth, Ted R. Hupp, J. Robert O’Neill, Olga Tucker, Andrew D. Beggs, Philippe Tanière, Sonia Puig, Gianmarco Contino, Tim Underwood, Robert Walker, Ben Grace, Jesper Lagergren, James Gossage, Andrew Davies, Fuju Chang, Ula Mahadeva, Vicky Goh, Francesca D. Ciccarelli, Grant Sanders, Richard Berrisford, David Tsz Chung Chan, Ed Cheong, Bhaskar Kumar, Loveena Sreedharan, Simon L. Parsons, Irshad Soomro, Philip Kaye, John Saunders, Laurence Lovat, Rehan Haidry, Michael A. Scott, Sharmila Sothi, Suzy Lishman, George B. Hanna, Christopher J. Peters, Krishna Moorthy, Anna M. Grabowska, Richard Turkington, Damian McManus, Helen G. Coleman, Russell Petty, Freddie Bartlett, Manuel Rodriguez‐Justo, Jo Spencer, Rebecca C. Fitzgerald, Francesca D. Ciccarelli
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.