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Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis

Research output: Contribution to journalArticle

Jamie M J Weaver, Caryn S Ross-innes, Nicholas Shannon, Andy G Lynch, Tim Forshew, Mariagnese Barbera, Muhammed Murtaza, Chin-ann J Ong, Pierre Lao-sirieix, Mark J Dunning, Laura Smith, Mike L Smith, Charlotte L Anderson, Benilton Carvalho, Maria O'donovan, Timothy J Underwood, Andrew P May, Nicola Grehan, Richard Hardwick, Jim Davies & 98 more Arusha Oloumi, Sam Aparicio, Carlos Caldas, Matthew D Eldridge, Paul A W Edwards, Nitzan Rosenfeld, Simon Tavar??, Rebecca C Fitzgerald, Stephen J Hayes, Ang Yeng, Anne-marie Lydon, Soney Dharmaprasad, Sandra Greer, Shaun Preston, Sarah Oakes, Vicki Save, Simon Paterson-brown, Olga Tucker, Derek Alderson, Philippe Taniere, Jamie Kelly, James Byrne, Donna Sharland, Nina Holling, Lisa Boulter, Fergus Noble, Bernard Stacey, Charles Crichton, Hugh Barr, Neil Shepherd, L Max Almond, Oliver Old, Jesper Lagergren, James Gossage, Andrew Davies, Robert Mason, Fuju Chang, Janine Zylstra, Grant Sanders, Tim Wheatley, Richard Berrisford, Tim Bracey, Catherine Harden, David Bunting, Tom Roques, Jenny Nobes, Suat Loo, Mike Lewis, Ed Cheong, Oliver Priest, Simon L Parsons, Irshad Soomro, Philip Kaye, John Saunders, Vincent Pang, Neil T Welch, James A Catton, John P Duffy, Krish Ragunath, Laurence Lovat, Rehan Haidry, Haroon Miah, Sarah Kerr, Victor Eneh, Rommel Butawan, Laszlo Igali, Hugo Ford, David Gilligan, Peter Safranek, Andy Hindmarsh, Vijayendran Sudjendran, Andy Metz, Nick Carroll, Michael Scott, Alison Cluroe, Ahmad Miremadi, Betania Mahler-araujo, Olga Knight, Barbara Nutzinger, Chris Peters, Zarah Abdullahi, Irene Debriram-beecham, Shalini Malhotra, Jason Crawte, Shona Macrae, Ayesha Noorani, Rachael Fels Elliott, Xiaodun Li, Lawrence Bower, Achilleas Achilleos, Jan Bornschein, Sebastian Zeki, Hamza Chettouh, Maria Secrier, Nadeera De Silva, Eleanor Gregson, Tsun-po Yang, J Robert O'neil

Original languageEnglish
Pages (from-to)837-843
Number of pages7
JournalNature Genetics
Issue number8
Publication statusPublished - Aug 2014

King's Authors


Cancer genome sequencing studies have identified numerous driver genes, but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from premalignant Barrett's esophagus to esophageal adenocarcinoma (EAC) provides an ideal model to study the ordering of somatic mutations. We identified recurrently mutated genes and assessed clonal structure using whole-genome sequencing and amplicon resequencing of 112 EACs. We next screened a cohort of 109 biopsies from 2 key transition points in the development of malignancy: benign metaplastic never-dysplastic Barrett's esophagus (NDBE; n = 66) and high-grade dysplasia (HGD; n = 43). Unexpectedly, the majority of recurrently mutated genes in EAC were also mutated in NDBE. Only TP53 and SMAD4 mutations occurred in a stage-specific manner, confined to HGD and EAC, respectively. Finally, we applied this knowledge to identify high-risk Barrett's esophagus in a new non-endoscopic test. In conclusion, mutations in EAC driver genes generally occur exceptionally early in disease development with profound implications for diagnostic and therapeutic strategies.

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