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.

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Acknowledgements

We thank the Human Research Tissue Bank, which is supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. This study was partly funded by a project grant from Cancer Research UK. R.C.F. has programmatic funding from the Medical Research Council and infrastructure support from the Biomedical Research Centre and the Experimental Medicine Centre. We would like to thank all the patients who took part in the study. We thank M. Dunning for his bioinformatics assistance. We thank the Edinburgh Experimental Cancer Medicine Centre.

Author information

Author notes

    • Caryn S Ross-Innes
    •  & Jennifer Becq

    These authors contributed equally to this work.

Affiliations

  1. Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.

    • Caryn S Ross-Innes
    • , Massimiliano di Pietro
    • , Jamie M J Weaver
    • , Rebecca C Fitzgerald
    • , Barbara Nutzinger
    • , Zarah Abdullahi
    • , Jason Crawte
    • , Shona MacRae
    • , Ayesha Noorani
    • , Rachael Fels Elliott
    • , Jan Bornschein
    • , Tsun-Po Yang
    • , Pierre Lao-Sirieix
    • , Nicola Grehan
    •  & Laura Smith
  2. Illumina, Chesterford Research Park, Little Chesterford, UK.

    • Jennifer Becq
    • , Andrew Warren
    • , R Keira Cheetham
    • , Helen Northen
    • , Sergii Ivakhno
    • , Miao He
    • , Zoya Kingsbury
    • , Mark Ross
    • , Sean Humphray
    •  & David Bentley
  3. Department of Histopathology, Addenbrooke's Hospital, Cambridge, UK.

    • Maria O'Donovan
    • , Shalini Malhotra
    • , Alison Cluroe
    • , Ahmad Miremadi
    •  & Betania Mahler-Araujo
  4. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.

    • Andy G Lynch
    • , Lawrence Bower
    • , Paul Edwards
    • , Simon Tavare
    • , Matthew Eldridge
    •  & Maria Secrier
  5. Salford Royal NHS Foundation Trust, Salford, UK.

    • Stephen J Hayes
    •  & Yeng Ang
  6. Faculty of Medical and Human Sciences, University of Manchester, UK.

    • Stephen J Hayes
    •  & Yeng Ang
  7. University Hospital of South Manchester, NHS Foundation Trust, Manchester, UK.

    • Ian Welch
  8. Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK.

    • Shaun Preston
    •  & Sarah Oakes
  9. Edinburgh Royal Infirmary, Edinburgh, UK.

    • Vicki Save
    •  & Richard Skipworth
  10. University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.

    • Olga Tucker
  11. Department of Computer Science, University of Oxford, UK.

    • Jim Davies
    • , Charles Crichton
    •  & Christian Schusterreiter
  12. Southampton General Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, UK.

    • Tim Underwood
    • , Fergus Noble
    • , Bernard Stacey
    • , Jamie Kelly
    • , James Byrne
    • , Annette Haydon
    • , Donna Sharland
    •  & Jack Owsley
  13. Gloucestershire Royal Hospital, Gloucestershire Hospitals NHS Foundation Trust, Gloucester, UK.

    • Hugh Barr
  14. Guy's and St Thomas' NHS Foundation Trust, London, UK.

    • Jesper Lagergren
    • , James Gossage
    • , Andrew Davies
    • , Robert Mason
    • , Fuju Chang
    • , Janine Zylstra
    •  & Chris Peters
  15. King's College Hospital, King's College Hospital NHS Foundation Trust, London, UK.

    • Jesper Lagergren
    • , James Gossage
    • , Andrew Davies
    • , Robert Mason
    • , Fuju Chang
    •  & Janine Zylstra
  16. Karolinska Institutet, Stockholm, Sweden.

    • Jesper Lagergren
  17. Plymouth Hospitals NHS Trust, Plymouth, UK.

    • Grant Sanders
    • , Tim Wheatley
    • , Richard Berrisford
    • , Tim Bracey
    • , Catherine Harden
    •  & David Bunting
  18. Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, UK.

    • Tom Roques
    • , Jenny Nobes
    • , Suat Loo
    • , Mike Lewis
    • , Ed Cheong
    •  & Oliver Priest
  19. Nottingham University Hospitals NHS Trust, Nottingham, UK.

    • Simon L Parsons
    • , Irshad Soomro
    • , Philip Kaye
    • , John Saunders
    • , Vincent Pang
    • , Neil T Welch
    • , James A Catton
    • , John P Duffy
    •  & Krish Ragunath
  20. University College London Hospitals NHS Foundation Trust, London, UK.

    • Laurence Lovat
    • , Rehan Haidry
    • , Haroon Miah
    • , Sarah Kerr
    • , Victor Eneh
    •  & Rommel Butawan
  21. Norfolk and Norwich University Hospital, NHS Foundation Trust, Norwich, UK.

    • Tom Roques
    • , Michael Lewis
    • , Edward Cheong
    • , Bhasker Kumar
    • , Laszlo Igali
    • , Sharon Walton
    •  & Adela Dann
  22. Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

    • Peter Safranek
    • , Andy Hindmarsh
    •  & Vijayendran Sudjendran
  23. Department of Pathology, Wythenshawe Hospital, Manchester, UK.

    • Michael Scott
  24. Edinburgh University, Edinburgh, UK.

    • J. Robert O'Neill
    •  & Kasia Adamczuk
  25. Peterborough Hospitals NHS Trust, Peterborough, UK.

    • Suzy Lishman
  26. University Hospital of North Midlands, NHS Foundation Trust, Stafford, UK.

    • Duncan Beardsmore
    •  & Sarah Dawson

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Contributions

R.C.F. conceived the overall study and takes responsibility for the data integrity. C.S.R.-I., J.B. and R.K.C. analyzed the data. C.S.R.-I. extracted the samples for patient AHM1051. A.W. developed the targeted sequencing data visualization tool. C.S.R.-I., J.B., R.K.C., H.N., J.M.J.W., M.R., S.H., D.B. and R.C.F. designed various aspects of the study. H.N. performed the TruSeq Custom Amplicon (TSCA) assay. C.S.R.-I., J.B. and A.G.L. performed the statistical analysis. M.d.P. collected endoscopic samples for patient AHM1051. M.O'D. and S.M. performed the histopathological diagnosis. S.I. developed the copy number pipeline, and R.K.C. and M.H. performed the copy number analysis. Z.K. ran the whole-genome sequencing of patient AHM1051. R.C.F., S.H., D.B. and M.R. supervised the study. C.S.R.-I., J.B., R.K.C. and R.C.F. wrote the manuscript. All authors approved the final version of the manuscript.

Competing interests

R.C.F. developed the Cytosponge technology, which has been licensed by MRC-Technology to Covidien. R.C.F. has no direct pecuniary interest. J.B., A.W., R.K.C., H.N., S.I., M.H., Z.K., M.R., S.H. and D.B. are employees of Illumina.

Corresponding author

Correspondence to Rebecca C Fitzgerald.

Integrated supplementary information

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–4 and Supplementary Tables 1–4.

Zip files

  1. 1.

    Supplementary Data Set

    Nebula: custom-made data browser to investigate and visualize the results from the 1,443 targets that were sequenced for 73 Barrett's esophagus samples from patient AHM1051.

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DOI

https://doi.org/10.1038/ng.3357

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