• A Corrigendum to this article was published on 31 January 2017

This article has been updated

Abstract

Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing owing to a lack of robust stratification methods. Whole-genome sequencing (WGS) analysis of 129 cases demonstrated that this is a heterogeneous cancer dominated by copy number alterations with frequent large-scale rearrangements. Co-amplification of receptor tyrosine kinases (RTKs) and/or downstream mitogenic activation is almost ubiquitous; thus tailored combination RTK inhibitor (RTKi) therapy might be required, as we demonstrate in vitro. However, mutational signatures showed three distinct molecular subtypes with potential therapeutic relevance, which we verified in an independent cohort (n = 87): (i) enrichment for BRCA signature with prevalent defects in the homologous recombination pathway; (ii) dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; and (iii) C>A/T mutational pattern with evidence of an aging imprint. These subtypes could be ascertained using a clinically applicable sequencing strategy (low coverage) as a basis for therapy selection.

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Change history

  • 19 September 2016

    In the version of this article initially published online, the mutation signature illustrations for S1 and S2 in Figure 3a were switched. Additionally, in the Online Methods, the text originally stated that structural variants were called using BWA-MEM, when it should have stated that these were called using BWA. These errors have been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

This paper is dedicated to Nadeera de Silva, who tragically and unexpectedly died while this paper was undergoing revision. He made an important contribution to this research, particularly bringing his clinical oncology perspective to bear on the translational relevance of the findings.

Whole-genome sequencing of esophageal adenocarcinoma samples was carried out in concert with the International Cancer Genome Consortium (ICGC) through the OCCAMS Consortium and was funded by program grants from Cancer Research UK (RG66287, RG81771, RG84119). We thank the ICGC members for their input on verification standards as part of the benchmarking exercise. We thank the Human Research Tissue Bank, which is supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, from Addenbrooke's Hospital and UCL. We also thank the University Hospital of Southampton Trust; the Southampton, Birmingham, Edinburgh and UCL Experimental Cancer Medicine Centres; and the QEHB charities. R.C.F. is funded by an NIHR Professorship (RG67258) and receives core funding from the Medical Research Council (RG84369) and infrastructure support from the Biomedical Research Centre (RG64237) and the Experimental Cancer Medicine Centre (RG62923). We acknowledge the support of the University of Cambridge, Cancer Research UK (C14303/A17197) and Hutchison Whampoa Limited. We thank P. Van Loo for providing the NGS version of ASCAT for copy number calling. We are grateful to all the patients who provided written consent for participation in this study and to the staff at all participating centres.

Some of the work was undertaken at UCLH/UCL, which received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. The views expressed in this publication are those of the authors and are not necessarily those of the Department of Health. The work at UCLH/UCL was also supported by the CRUK UCL Early Cancer Medicine Centre.

Author information

Author notes

    • Maria Secrier
    •  & Xiaodun Li

    These authors contributed equally to this work.

Affiliations

  1. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.

    • Maria Secrier
    • , Matthew D Eldridge
    • , Lawrence Bower
    • , Achilleas Achilleos
    • , Andy G Lynch
    • , Simon Tavaré
    •  & Mike L Smith
  2. Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.

    • Xiaodun Li
    • , Nadeera de Silva
    • , Gianmarco Contino
    • , Jan Bornschein
    • , Shona MacRae
    • , Nicola Grehan
    • , Maria O'Donovan
    • , Ahmad Miremadi
    • , Tsun-Po Yang
    • , Hamza Chettouh
    • , Jason Crawte
    • , Núria Galeano-Dalmau
    • , Barbara Nutzinger
    • , Rebecca C Fitzgerald
    • , Ayesha Noorani
    • , Rachael Fels Elliott
    • , Jamie Weaver
    • , Caryn Ross-Innes
    • , Laura Smith
    • , Zarah Abdullahi
    •  & Rachel de la Rue
  3. Department of Histopathology, Cambridge University Hospital NHS Trust, Cambridge, UK.

    • Maria O'Donovan
    • , Ahmad Miremadi
    • , Alison Cluroe
    •  & Shalini Malhotra
  4. Queen's Medical Centre, University of Nottingham, Nottingham, UK.

    • Anna Grabowska
  5. Department of Oesophagogastric Surgery, Nottingham University Hospitals NHS Trust, Nottingham, UK.

    • John Saunders
    • , Simon L Parsons
    • , Irshad Soomro
    • , Philip Kaye
    •  & Pamela Collier
  6. Cancer Sciences Division, University of Southampton, Southampton, UK.

    • Tim Underwood
  7. University Hospital Southampton NHS Foundation Trust, Southampton, UK.

    • Tim Underwood
    • , Fergus Noble
    •  & Jack Owsley
  8. Department of Genetics and Computational Biology, QIMR Berghofer, Herston, Queensland, Australia.

    • Nicola Waddell
    • , John V Pearson
    • , Katia Nones
    •  & Ann-Marie Patch
  9. Surgical Oncology Group, School of Medicine, University of Queensland, Translational Research Institute at the Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland, Australia.

    • Andrew P Barbour
  10. Department of Surgery, School of Medicine, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland, Australia.

    • Andrew P Barbour
  11. Department of Pathology, University of Cambridge, Cambridge, UK.

    • Paul A W Edwards
  12. Oesophago-Gastric Unit, Addenbrooke's Hospital, Cambridge, UK.

    • Richard Hardwick
    •  & Hugo Ford
  13. Oxford ComLab, University of Oxford, Oxford, UK.

    • Jim Davies
  14. Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK.

    • Richard Turkington
  15. Salford Royal NHS Foundation Trust, Salford, UK.

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

    • Stephen J Hayes
  17. Wigan and Leigh NHS Foundation Trust, Wigan, Manchester, UK.

    • Yeng Ang
  18. GI Science Centre, University of Manchester, Manchester, UK.

    • Yeng Ang
  19. Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK.

    • Shaun R Preston
    • , Sarah Oakes
    •  & Izhar Bagwan
  20. The Royal Infirmary of Edinburgh (NHS Lothian), Edinburgh, UK.

    • Vicki Save
    • , Richard J E Skipworth
    • , Ted R Hupp
    •  & J Robert O'Neill
  21. Edinburgh University, Edinburgh, UK.

    • J Robert O'Neill
  22. University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.

    • Olga Tucker
    •  & Philippe Taniere
  23. Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.

    • Olga Tucker
  24. University College London, London, UK.

    • Laurence Lovat
    • , Rehan Haidry
    •  & Victor Eneh
  25. Department of Computer Science, University of Oxford, Oxford, UK.

    • Charles Crichton
  26. Gloucester Royal Hospital, Gloucester, UK.

    • Hugh Barr
    • , Neil Shepherd
    •  & Oliver Old
  27. St Thomas's Hospital, London, UK.

    • Jesper Lagergren
    • , James Gossage
    • , Andrew Davies
    • , Fuju Chang
    •  & Janine Zylstra
  28. King's College London, London, UK.

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

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

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

    • Mike Lewis
    • , Ed Cheong
    •  & Bhaskar Kumar
  32. Norfolk and Waveney Cellular Pathology Network, Norwich, UK.

    • Laszlo Igali
  33. University Hospital of South Manchester NHS Foundation Trust, Wythenshawe, Manchester, UK.

    • Ian Welch
    •  & Michael Scott
  34. University Hospitals Coventry and Warwickshire NHS, Trust, Coventry, UK.

    • Shamila Sothi
    •  & Sari Suortamo
  35. Peterborough Hospitals NHS Trust, Peterborough City Hospital, Peterborough, UK.

    • Suzy Lishman
  36. Royal Stoke University Hospital, UHNM NHS Trust, Stoke, UK.

    • Duncan Beardsmore
  37. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Hayley E Francies
    •  & Mathew J Garnett
  38. Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.

    • John V Pearson
    • , Katia Nones
    • , Ann-Marie Patch
    •  & Sean M Grimmond
  39. Victorian Comprehensive Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia.

    • Sean M Grimmond

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  1. the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium

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Contributions

R.C.F. conceived the overall study. M.S., X.L. and P.A.W.E. analyzed the data. R.C.F., M.S., X.L., N.d.S., P.A.W.E. and A.G.L. conceived and designed the experiments. M.S. performed the statistical analysis. X.L., G.C., S.M., M.O., A.M., J.C. and N.G.-D. performed the experiments. M.D.E. performed benchmarking studies on the variant calls, and implemented and ran several variant-calling and analysis pipelines. G.C. contributed to the structural variant analysis. J.B. contributed expression data and curated the clinical data collection. S.M. and N.G. coordinated sample processing with clinical centers and was responsible for sample collections. T.-P.Y. performed the BFB analysis. L.B. ran the variant-calling pipelines. H.C. contributed to the RTK analysis. A.G., J.S. and T.U. contributed cell lines. N.W. and A.P.B. contributed sequencing data for validation. B.N. coordinated data and tissue collection from centers for the study. A.A. helped develop the copy-number-calling pipeline. R.C.F. and S.T. jointly supervised the research. M.S., N.d.S., X.L. and R.C.F. wrote the manuscript. All authors approved the final version of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Rebecca C Fitzgerald.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–28, Supplementary Tables 1, 2, 4–9, 11 and 12 and Supplementary Note

Excel files

  1. 1.

    Supplementary Table 3

    Significantly deleted loci in the cohort according to GISTIC2.0. Loci with residual q-value

  2. 2.

    Supplementary Table 10

    Microsatellite instability analysis results. The potentially microsatellite unstable samples that were removed from the analysis are highlighted at the top.

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DOI

https://doi.org/10.1038/ng.3659

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