Abstract

Esophageal adenocarcinoma (EAC) is a poor-prognosis cancer type with rapidly rising incidence. Understanding of the genetic events driving EAC development is limited, and there are few molecular biomarkers for prognostication or therapeutics. Using a cohort of 551 genomically characterized EACs with matched RNA sequencing data, we discovered 77 EAC driver genes and 21 noncoding driver elements. We identified a mean of 4.4 driver events per tumor, which were derived more commonly from mutations than copy number alterations, and compared the prevelence of these mutations to the exome-wide mutational excess calculated using non-synonymous to synonymous mutation ratios (dN/dS). We observed mutual exclusivity or co-occurrence of events within and between several dysregulated EAC pathways, a result suggestive of strong functional relationships. Indicators of poor prognosis (SMAD4 and GATA4) were verified in independent cohorts with significant predictive value. Over 50% of EACs contained sensitizing events for CDK4 and CDK6 inhibitors, which were highly correlated with clinically relevant sensitivity in a panel of EAC cell lines and organoids.

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Code availability

Code associated with the analysis is available upon request.

Data availability

The WGS and RNA expression data can be found at the European Genome-phenome Archive under accession numbers EGAD00001004417 and EGAD00001004423, respectively.

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Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Acknowledgements

We thank A. J. Bass and N. Waddell for providing data in Dulak et al.19 and Nones et al.20, respectively, which were also included in our previous publication18. Inclusion of these data allowed for augmentation of our ICGC cohort and greater sensitivity for the detection of EAC driver variants. OCCAMS was funded by a Programme Grant from Cancer Research UK (RG66287), and the laboratory of R.C.F. is funded by a Core Programme Grant from the Medical Research Council. We thank the Human Research Tissue Bank, which is supported by the UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre, from Addenbrooke’s Hospital. Additional infrastructure support was provided from the Cancer Research UK–funded Experimental Cancer Medicine Centre.

Author information

Affiliations

  1. MRC cancer unit, Hutchison/MRC research Centre, University of Cambridge, Cambridge, UK

    • Alexander M. Frankell
    • , Xiaodun Li
    • , Gianmarco Contino
    • , Sarah Killcoyne
    • , Sujath Abbas
    • , Emma Ococks
    • , Nicola Grehan
    • , James Mok
    • , Shona MacRae
    • , Rebecca C. Fitzgerald
    • , Ayesha Noorani
    • , Paul A. W. Edwards
    • , Nicola Grehan
    • , Barbara Nutzinger
    • , Caitriona Hughes
    • , Elwira Fidziukiewicz
    • , Shona MacRae
    • , Alex Northrop
    • , Gianmarco Contino
    • , Xiaodun Li
    • , Rachel de la Rue
    • , Annalise Katz-Summercorn
    • , Sujath Abbas
    • , Daniel Loureda
    • , Ahmad Miremadi
    • , Shalini Malhotra
    • , Monika Tripathi
    •  & Rebecca C. Fitzgerald
  2. Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK

    • SriGanesh Jammula
    • , Juliane Perner
    • , Lawrence Bower
    • , Ginny Devonshire
    • , Matthew D. Eldridge
    • , Simon Tavaré
    • , Paul A. W. Edwards
    • , Simon Tavaré
    • , Andy G. Lynch
    • , Matthew Eldridge
    • , Ginny Devonshire
    • , Juliane Perner
    •  & SriGanesh Jammula
  3. European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK

    • Sarah Killcoyne
  4. Department of Histopathology, Cambridge University Hospital NHS Trust, Cambridge, UK

    • Maria O’Donovan
    • , Ahmad Miremadi
    • , Shalini Malhotra
    •  & Monika Tripathi
  5. Department of Genetics, Evolution and Environment, UCL Genetics Institute, University College London, London, UK

    • Maria Secrier
  6. Department of Computer Science, University of Oxford, Oxford, UK

    • Jim Davies
    •  & Charles Crichton
  7. Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

    • Nick Carroll
    • , Peter Safranek
    • , Andrew Hindmarsh
    •  & Vijayendran Sujendran
  8. Salford Royal NHS Foundation Trust, Salford, UK

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

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

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

    • Yeng Ang
    •  & Andrew Sharrocks
  12. Royal Surrey County Hospital NHS Foundation Trust, Guildford, UK

    • Shaun R. Preston
    • , Sarah Oakes
    •  & Izhar Bagwan
  13. Edinburgh Royal Infirmary, Edinburgh, UK

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

    • J. Robert O’Neill
  15. University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK

    • Olga Tucker
    • , Andrew Beggs
    • , Philippe Taniere
    •  & Sonia Puig
  16. Heart of England NHS Foundation Trust, Birmingham, UK

    • Olga Tucker
  17. Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK

    • Andrew Beggs
  18. University Hospital Southampton NHS Foundation Trust, Southampton, UK

    • Timothy J. Underwood
    • , Robert C. Walker
    •  & Ben L. Grace
  19. Cancer Sciences Division, University of Southampton, Southampton, UK

    • Timothy J. Underwood
    •  & Robert C. Walker
  20. Gloucester Royal Hospital, Gloucester, UK

    • Hugh Barr
    • , Neil Shepherd
    •  & Oliver Old
  21. Guy’s and St Thomas’s NHS Foundation Trust, London, UK

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

    • Jesper Lagergren
  23. King’s College London, London, UK

    • James Gossage
    • , Andrew Davies
    • , Fuju Chang
    • , Janine Zylstra
    • , Vicky Goh
    •  & Francesca D. Ciccarelli
  24. Plymouth Hospitals NHS Trust, Plymouth, UK

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

    • Mike Lewis
    • , Ed Cheong
    •  & Bhaskar Kumar
  26. Nottingham University Hospitals NHS Trust, Nottingham, UK

    • Simon L. Parsons
    • , Irshad Soomro
    • , Philip Kaye
    •  & John Saunders
  27. University College London, London, UK

    • Laurence Lovat
    •  & Rehan Haidry
  28. Norfolk and Waveney Cellular Pathology Network, Norwich, UK

    • Laszlo Igali
  29. Wythenshawe Hospital, Manchester, UK

    • Michael Scott
  30. University Hospitals Coventry and Warwickshire NHS, Trust, Coventry, UK

    • Sharmila Sothi
    •  & Sari Suortamo
  31. Peterborough Hospitals NHS Trust, Peterborough City Hospital, Peterborough, UK

    • Suzy Lishman
  32. Department of Surgery and Cancer, Imperial College London, London, UK

    • George B. Hanna
    • , Krishna Moorthy
    •  & Christopher J. Peters
  33. Queen’s Medical Centre, University of Nottingham, Nottingham, UK

    • Anna Grabowska
  34. Centre for Cancer Research and Cell Biology, Queen’s University Belfast, Belfast, UK

    • Richard Turkington
    • , Damian McManus
    •  & Helen Coleman
  35. Queen’s Hospital, Romford, UK

    • David Khoo
    •  & Will Fickling

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Consortia

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

Contributions

R.C.F. and A.M.F. conceived the overall study. A.M.F. and S.J. analyzed the genomic data and performed statistical analyses. R.C.F., A.M.F. and X.L. designed the experiments. A.M.F., X.L. and J.M. performed the experiments. G.C. contributed to the structural variant analysis and data visualization. S.K. helped compile the clinical data and aided in statistical analyses. J.P. and S.A. produced and performed quality control on the RNA-seq data. E.O. aided in WGS of EAC cell lines. S.M. and N.G. coordinated the clinical centers and were responsible for sample collection. M.D.E. benchmarked our mutation-calling pipelines. M.O. led the pathological sample quality control for sequencing. L.B. and G.D. constructed and managed the sequencing alignment and variant-calling pipelines. R.C.F. and S.T. supervised the research. R.C.F. and S.T. obtained funding. A.M.F. and R.C.F. wrote the manuscript. All authors approved the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Rebecca C. Fitzgerald.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–12, Supplementary Tables 8, 10, 12 and 13, and Supplementary Note

  2. Reporting Summary

  3. Supplementary Tables 1–7, 9 and 11

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https://doi.org/10.1038/s41588-018-0331-5