Abstract

The evolutionary events that cause colorectal adenomas (benign) to progress to carcinomas (malignant) remain largely undetermined. Using multi-region genome and exome sequencing of 24 benign and malignant colorectal tumours, we investigate the evolutionary fitness landscape occupied by these neoplasms. Unlike carcinomas, advanced adenomas frequently harbour sub-clonal driver mutations—considered to be functionally important in the carcinogenic process—that have not swept to fixation, and have relatively high genetic heterogeneity. Carcinomas are distinguished from adenomas by widespread aneusomies that are usually clonal and often accrue in a ‘punctuated’ fashion. We conclude that adenomas evolve across an undulating fitness landscape, whereas carcinomas occupy a sharper fitness peak, probably owing to stabilizing selection.

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Data availability

Raw data are available via the European Genome-Phenome Archive (https://ega-archive.org/) accession code: EGAS00001003066.

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Acknowledgements

S.J.L., T.A.G. (A19771) and I.P.M.T. (A27327) are funded by Cancer Research UK. We acknowledge core funding provided to the Wellcome Trust Centre for Human Genetics from the Wellcome Trust (090532/Z/09/Z). T.A.G. and S.J.L. were also supported by the Bowel and Cancer Research small grant scheme. T.A.G. was also supported by the Wellcome Trust (202778/Z/16/Z). V.M. was supported in part by funding from the Wellcome Trust (098051). M. Kovac was supported by the Krebsliga beider Basel (grant no. KLBB-12-2013) and the University of Basel (‘Förderung exzellenter Nachwuchsforschender’). A-M.B. also acknowledges funding from Cancer Research UK (A14895). D.C.W. is supported by the Li Ka Shing Foundation. X.J. and I.P.M.T. are supported by an ERC advanced grant (EVOCAN-340560). The S:CORT study is funded by the MRC and Cancer Research UK. K.H is supported by Krebsliga Zentralschweiz. A.S. is supported by the Wellcome Trust (202778/B/16/Z), Cancer Research UK (A22909) and the Chris Rokos Fellowship in Evolution and Cancer. This work was also supported a Wellcome Trust award to the Centre for Evolution and Cancer (105104/Z/14/Z). J.E.E. was funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). V.H.K. was funded by the Swiss National Science Foundation (P2SKP3_168322 / 1 and P2SKP3_168322 / 2). D.T. acknowledges funding from the EPSRC (grant no.: EP/F500351/1).

Author information

Author notes

  1. A list of participants and their affiliations appears at the end of the paper.

Affiliations

  1. Evolution and Cancer Laboratory, Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    • William Cross
    • , Daniel Temko
    • , Ann-Marie Baker
    • , Pierre Martinez
    •  & Trevor A. Graham
  2. Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    • William Cross
    • , Michal Kovac
    • , Viktor H. Koelzer
    • , Enric Domingo
    • , Yun Feng
    •  & Ian Tomlinson
  3. Bone Tumour Reference Center at the Institute of Pathology, University Hospital Basel, Basel, Switzerland

    • Michal Kovac
  4. Organismal and Evolutionary Biology Research Programme, Department of Computer Science, Institute of Biotechnology, Helsinki Institute for Information Technology HIIT, University of Helsinki, Helsinki, Finland

    • Ville Mustonen
  5. CoMPLEX, Department of Computer Science, University College London, London, UK

    • Daniel Temko
  6. Gastrointestinal Stem Cell Biology Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    • Hayley Davis
    • , Sujata Biswas
    • , Simon Leedham
    •  & Simon J. Leedham
  7. Cancer Bioinfomatics Group, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK

    • Roland Arnold
    •  & Jean-Baptiste Cazier
  8. Gastrointestinal Cancer Genetics Laboratory, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK

    • Laura Chegwidden
    •  & Claire Palles
  9. Integrated Mathematical Oncology Department, Moffitt Comprehensive Cancer Centre, Tampa, FL, USA

    • Chandler Gatenbee
    •  & Alexander R. Anderson
  10. Institute of Pathology, University of Bern, Bern, Switzerland

    • Viktor H. Koelzer
  11. Cancer Genetics and Evolution Laboratory, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK

    • Xiaowei Jiang
    • , Ian Tomlinson
    •  & Ian P. M. Tomlinson
  12. Big Data Institute, University of Oxford, Oxford, UK

    • Dan J. Woodcock
    • , Chris Holmes
    •  & David C. Wedge
  13. Institute of Mathematics and Physics, Faculty of Mechanical Engineering, Slovak University of Technology in Bratislava, Bratislava, Slovakia

    • Monika Kovacova
  14. Department of Oncology, University of Oxford, Oxford, UK

    • Tim Maughan
    • , Francesca Buffa
    • , Enric Domingo
    • , Andrew Blake
    • , Geoff Higgins
    • , Tim Maughan
    • , Gillies McKenna
    • , Anna Schuh
    •  & Ricky Sharma
  15. Department of Research Pathology, Cancer Institute, University College London, London, UK

    • Marnix Jansen
    •  & Manuel Rodriguez-Justo
  16. Department of Surgery, University Hospitals Birmingham, Birmingham, UK

    • Simon Bach
    • , Andrew Beggs
    • , Dion Morton
    •  & Shazad Ashraf
  17. Department of Colorectal Surgery, Cancer Centre, Churchill Hospital, Oxford University Hospital NHS Foundation Trust, Oxford, UK

    • Richard Guy
    •  & Christopher Cunningham
  18. Translational Gastroenterology Unit, University of Oxford, John Radcliffe Hospital, Oxford, UK

    • Simon Leedham
    • , James E. East
    •  & Simon J. Leedham
  19. Ludwig Institute for Cancer Research, Nuffield Department of Medicine, University of Oxford, Oxford, UK

    • Lai Mun Wang
  20. Institute for Medical Genetics and Pathology, University Hospital Basel, Basel, Switzerland

    • Karl Heinimann
  21. Department of Biomedicine, University of Basel, Basel, Switzerland

    • Karl Heinimann
  22. Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK

    • Andrea Sottoriva
  23. Department of Histopathology, University Hospitals Birmingham, Birmingham, UK

    • Ian P. M. Tomlinson
  24. Centre for Trials Research, Cardiff University, Cardiff, UK

    • Richard Adams
  25. Clinical Trials Unit, University College London, London, UK

    • Louise Brown
    •  & Rick Kaplan
  26. Department of Statistics, University of Oxford, Oxford, UK

    • Che-Hsi Wu
    •  & Chris Holmes
  27. Wellcome Trust Sanger Institute, Hinxton, UK

    • Ekaterina Chatzpili
    •  & Ultan McDermott
  28. Institute of Cancer and Pathology, Faculty of Medicine and Health, University of Leeds, Leeds, UK

    • Susan Richman
    • , Phil Quirke
    • , David Sebag-Montefiore
    • , Matt Seymour
    •  & Nicholas West
  29. School of Medicine, Queens University Belfast, Belfast, UK

    • Philip Dunne
    • , Paul Harkin
    • , Richard Kennedy
    • , Mark Lawler
    • , Manuel Salto-Tellez
    •  & Richard Wilson
  30. Department of General Surgery, Manchester Royal Infirmary, Manchester, UK

    • Jim Hill
  31. European Alliance for Personalised Medicine, Brussels, Belgium

    • Denis Horgan
  32. Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK

    • Gary Middleton
  33. Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK

    • Graeme Murray
    •  & Les Samuel
  34. Institute of Cancer Policy, Kings College London, London, UK

    • Richard Sullivan

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Consortia

  1. The S:CORT Consortium

Contributions

I.P.M.T., T.A.G. and S.J.L. conceived and designed the study. R.G., J.E.E., L.M.W., K.H., S.J.L. and I.P.M.T. provided the samples. H.D., A.-M.B., S.B. and L.C. performed the experiments. W.C., M. Kovac, V.M., P.M., R.A. and D.C.W. performed the bioinformatics analysis. W.C. and D.T. performed the mathematical analysis. C.G., A.R.A. and V.H.K. performed the image analysis. M.J., M.R.-J. and L.M.W. performed the pathology assessment. E.D., T.M. and the S:CORT consortium provided reference data. W.C., M. Kovac, V.M., D.T., R.A., V.H.K., X.J., D.C.W., Y.F., M.Kovacova, S.A., A.S., S.J.L., T.A.G. and I.P.M.T. analysed the data. W.C., A.S., S.J.L., T.A.G. and I.P.M.T. performed the evolutionary analysis. W.C., T.A.G. and I.P.M.T. wrote the manuscript with input from all authors.

Competing interests

The authors declare no competing interests.

Corresponding authors

Correspondence to Trevor A. Graham or Ian P. M. Tomlinson.

Supplementary information

  1. Supplementary Information

    Supplementary figures 1–9; Supplementary modelling; Supplementary table legends

  2. Reporting Summary

  3. Supplementary tables

    Supplementary tables 1–7

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DOI

https://doi.org/10.1038/s41559-018-0642-z