Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance (original) (raw)

Change history

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.

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Author notes

  1. Maria Secrier, Xiaodun Li, John V Pearson, Katia Nones, Ann-Marie Patch and Sean M Grimmond: These authors contributed equally to this work.

Authors and 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

Authors

  1. Maria Secrier
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  2. Xiaodun Li
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  3. Nadeera de Silva
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  4. Matthew D Eldridge
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  5. Gianmarco Contino
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  6. Jan Bornschein
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  7. Shona MacRae
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  8. Nicola Grehan
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  9. Maria O'Donovan
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  10. Ahmad Miremadi
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  11. Tsun-Po Yang
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  12. Lawrence Bower
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  13. Hamza Chettouh
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  14. Jason Crawte
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  15. Núria Galeano-Dalmau
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  16. Anna Grabowska
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  17. John Saunders
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  18. Tim Underwood
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  19. Nicola Waddell
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  20. Andrew P Barbour
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  21. Barbara Nutzinger
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  22. Achilleas Achilleos
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  23. Paul A W Edwards
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  24. Andy G Lynch
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  25. Simon Tavaré
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  26. Rebecca C Fitzgerald
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Consortia

the Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium

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.

Corresponding author

Correspondence toRebecca C Fitzgerald.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–28, Supplementary Tables 1, 2, 4–9, 11 and 12 and Supplementary Note (PDF 5505 kb)

Supplementary Table 3

Significantly deleted loci in the cohort according to GISTIC2.0. Loci with residual q-value (XLSX 13 kb)

Supplementary Table 10

Microsatellite instability analysis results. The potentially microsatellite unstable samples that were removed from the analysis are highlighted at the top. (XLSX 13 kb)

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Secrier, M., Li, X., de Silva, N. et al. Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance.Nat Genet 48, 1131–1141 (2016). https://doi.org/10.1038/ng.3659

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