Whole-genome sequencing provides new insights into the clonal architecture of Barrett's esophagus and esophageal adenocarcinoma

Caryn S. Ross-Innes, Jennifer Becq, Andrew Warren, R. Keira Cheetham, Helen Northen, Maria O'Donovan, Shalini Malhotra, Massimiliano Di Pietro, Sergii Ivakhno, Miao He, Jamie M.J. Weaver, Andy G. Lynch, Zoya Kingsbury, Mark Ross, Sean Humphray, David Bentley, Rebecca C. Fitzgerald*, Stephen J. Hayes, Yeng Ang, Ian WelchShaun Preston, Sarah Oakes, Vicki Save, Richard Skipworth, Olga Tucker, Jim Davies, Charles Crichton, Christian Schusterreiter, Tim Underwood, Fergus Noble, Bernard Stacey, Jamie Kelly, James Byrne, Annette Haydon, Donna Sharland, Jack Owsley, Hugh Barr, 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 Welch, James A. Catton, John P. Duffy, Krish Ragunath, Laurence Lovat, Rehan Haidry, Haroon Miah, Sarah Kerr, Victor Eneh, Rommel Butawan, Michael Lewis, Edward Cheong, Bhasker Kumar, Laszlo Igali, Sharon Walton, Adela Dann, Peter Safranek, Andy Hindmarsh, Vijayendran Sudjendran, Michael Scott, Alison Cluroe, Ahmad Miremadi, Betania Mahler-Araujo, Barbara Nutzinger, Chris Peters, Zarah Abdullahi, Jason Crawte, Shona MacRae, Ayesha Noorani, Rachael Fels Elliott, Lawrence Bower, Paul Edwards, Simon Tavare, Matthew Eldridge, Jan Bornschein, Maria Secrier, Tsun Po Yang, J. Robert O'Neill, Kasia Adamczuk, Pierre Lao-Sirieix, Nicola Grehan, Laura Smith, Suzy Lishman, Duncan Beardsmore, Sarah Dawson

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

213 Citations (Scopus)

Abstract

The molecular genetic relationship between esophageal adenocarcinoma (EAC) and its precursor lesion, Barrett's esophagus, is poorly understood. Using whole-genome sequencing on 23 paired Barrett's esophagus and EAC samples, together with one in-depth Barrett's esophagus case study sampled over time and space, we have provided the following new insights: (i) Barrett's esophagus is polyclonal and highly mutated even in the absence of dysplasia; (ii) when cancer develops, copy number increases and heterogeneity persists such that the spectrum of mutations often shows surprisingly little overlap between EAC and adjacent Barrett's esophagus; and (iii) despite differences in specific coding mutations, the mutational context suggests a common causative insult underlying these two conditions. From a clinical perspective, the histopathological assessment of dysplasia appears to be a poor reflection of the molecular disarray within the Barrett's epithelium, and a molecular Cytosponge technique overcomes sampling bias and has the capacity to reflect the entire clonal architecture.

Original languageEnglish
Pages (from-to)1038-1046
Number of pages9
JournalNature Genetics
Volume47
Issue number9
DOIs
Publication statusPublished - 27 Aug 2015

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