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The evolutionary landscape of colorectal tumorigenesis

Nature Ecology & Evolution volume 2, pages 1661–1672 (2018)Cite this article

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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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Fig. 1: Mutation burdens in CRAs and CRCs.
Fig. 2: Phylogenetic analysis of CRAs and MSS CRCs.
Fig. 3: CNAs in CRAs and MSS CRCs.
Fig. 4: Geography of CRCs.
Fig. 5: CNA timings.

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.

Authors and 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

Authors
  1. William Cross
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  2. Michal Kovac
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  3. Ville Mustonen
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  4. Daniel Temko
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  5. Hayley Davis
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  6. Ann-Marie Baker
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  7. Sujata Biswas
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  8. Roland Arnold
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  9. Laura Chegwidden
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  10. Chandler Gatenbee
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  11. Alexander R. Anderson
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  12. Viktor H. Koelzer
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  13. Pierre Martinez
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  14. Xiaowei Jiang
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  15. Enric Domingo
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  16. Dan J. Woodcock
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  17. Yun Feng
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  18. Monika Kovacova
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  19. Tim Maughan
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  20. Marnix Jansen
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  21. Manuel Rodriguez-Justo
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  22. Shazad Ashraf
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  23. Richard Guy
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  24. Christopher Cunningham
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Consortia

The S:CORT Consortium

  • Richard Adams
  • , Simon Bach
  • , Andrew Beggs
  • , Louise Brown
  • , Francesca Buffa
  • , Jean-Baptiste Cazier
  • , Enric Domingo
  • , Andrew Blake
  • , Che-Hsi Wu
  • , Ekaterina Chatzpili
  • , Susan Richman
  • , Philip Dunne
  • , Paul Harkin
  • , Geoff Higgins
  • , Jim Hill
  • , Chris Holmes
  • , Denis Horgan
  • , Rick Kaplan
  • , Richard Kennedy
  • , Mark Lawler
  • , Simon Leedham
  • , Tim Maughan
  • , Ultan McDermott
  • , Gillies McKenna
  • , Gary Middleton
  • , Dion Morton
  • , Graeme Murray
  • , Phil Quirke
  • , Manuel Salto-Tellez
  • , Les Samuel
  • , Anna Schuh
  • , David Sebag-Montefiore
  • , Matt Seymour
  • , Ricky Sharma
  • , Richard Sullivan
  • , Ian Tomlinson
  • , Nicholas West
  •  & Richard Wilson

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.

Corresponding authors

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

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

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Cross, W., Kovac, M., Mustonen, V. et al. The evolutionary landscape of colorectal tumorigenesis. Nat Ecol Evol 2, 1661–1672 (2018). https://doi.org/10.1038/s41559-018-0642-z

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