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Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue

Nature Genetics volume 47, pages 367372 (2015) | Download Citation

  • A Corrigendum to this article was published on 27 May 2015

This article has been updated


Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases.

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Change history

  • 05 May 2015

    In the version of this article initially published, author Manasa Ramakrishna was omitted from the author list. The error has been corrected in the PDF and HTML versions of this article.


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This work was funded by Cancer Research UK (grant C5047/A14835), the Dallaglio Foundation and the Wellcome Trust. We also acknowledge support from the Bob Champion Cancer Trust, the Orchid Cancer Appeal, the RoseTrees Trust, the North West Cancer Research Fund, Big C, the King family, the Grand Charity of Freemasons, and the Research Foundation Flanders (FWO). We thank D. Holland from the Infrastructure Management Team and P. Clapham from the Informatics Systems Group at the Wellcome Trust Sanger Institute. We acknowledge the Biomedical Research Centre at the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, supported by the National Institute for Health Research. We acknowledge support from the National Cancer Research Prostate Cancer: Mechanisms of Progression and Treatment (PROMPT) collaborative (grant G0500966/75466). We thank the National Institute for Health Research, Hutchison Whampoa Limited and the Human Research Tissue Bank (Addenbrooke's Hospital), the Cancer Research UK Cambridge Research Institute Histopathology, the In-situ Hybridisation Core Facility, the Genomics Core Facility Cambridge and the Cambridge University Hospitals Media Studio.

Author information

Author notes

    • Colin S Cooper
    • , Rosalind Eeles
    • , David C Wedge
    • , Peter Van Loo
    • , Anne Y Warren
    • , Christopher S Foster
    • , Hayley C Whitaker
    • , Ultan McDermott
    • , Daniel S Brewer
    •  & David E Neal

    These authors contributed equally to this work.

    • Colin S Cooper
    • , Rosalind Eeles
    • , Christopher S Foster
    • , Ultan McDermott
    • , Daniel S Brewer
    •  & David E Neal

    These authors jointly supervised this work.


  1. Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.

    • Colin S Cooper
    • , Rosalind Eeles
    • , Niedzica Camacho
    • , Sandra Edwards
    • , Zsofia Kote-Jarai
    • , Sue Merson
    • , Daniel Leongamornlert
    • , Lucy Matthews
    •  & Daniel S Brewer
  2. Department of Biological Sciences, University of East Anglia, Norwich, UK.

    • Colin S Cooper
  3. Norwich Medical School, University of East Anglia, Norwich, UK.

    • Colin S Cooper
    • , Jeremy Clark
    • , Rachel Hurst
    •  & Daniel S Brewer
  4. Royal Marsden NHS Foundation Trust, London and Sutton, UK.

    • Rosalind Eeles
    • , Nening Dennis
    • , Sarah Thomas
    • , Steven Hazell
    • , Naomi Livni
    • , Cyril Fisher
    • , Christopher Ogden
    • , Pardeep Kumar
    • , Alan Thompson
    • , Christopher Woodhouse
    • , David Nicol
    • , Erik Mayer
    •  & Tim Dudderidge
  5. Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, UK.

    • David C Wedge
    • , Peter Van Loo
    • , Gunes Gundem
    • , Ludmil B Alexandrov
    • , Barbara Kremeyer
    • , Adam Butler
    • , Jorge Zamora
    • , Serena Nik-Zainal
    • , Manasa Ramakrishna
    • , Sarah O'Meara
    • , Susanna Cooke
    • , Keiran Raine
    • , David Jones
    • , Andrew Menzies
    • , Lucy Stebbings
    • , Jon Hinton
    • , Jon Teague
    • , Stuart McLaren
    • , Laura Mudie
    • , Claire Hardy
    • , Elizabeth Anderson
    • , Olivia Joseph
    • , Victoria Goody
    • , Ben Robinson
    • , Mark Maddison
    • , Stephen Gamble
    • , Peter Campbell
    • , Andrew Futreal
    • , Michael R Stratton
    •  & Ultan McDermott
  6. Human Genome Laboratory, Department of Human Genetics, VIB and KU Leuven, Leuven, Belgium.

    • Peter Van Loo
  7. Cancer Research UK London Research Institute, London, UK.

    • Peter Van Loo
  8. Statistics and Computational Biology Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge, UK.

    • Andrew G Lynch
  9. Urological Research Laboratory, Cancer Research UK Cambridge Research Institute, Cambridge, UK.

    • Charlie E Massie
    • , Jonathan Kay
    • , Hayley J Luxton
    • , Nimish C Shah
    • , Vincent Gnanapragasam
    • , Hayley C Whitaker
    •  & David E Neal
  10. Department of Histopathology, St. Georges Hospital, London, UK.

    • Cathy Corbishley
  11. Institute of Food Research, Norwich Research Park, Norwich, UK.

    • Richard Mithen
  12. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

    • Robert G Bristow
    •  & Paul C Boutros
  13. Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.

    • Robert G Bristow
    •  & Michael Fraser
  14. Princess Margaret Cancer Centre–University Health Network, Toronto, Ontario, Canada.

    • Robert G Bristow
    •  & Michael Fraser
  15. Informatics and Bio-Computing, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

    • Paul C Boutros
  16. Department Pharmacology & Toxicology, University of Toronto, Toronto, Ontario, Canada.

    • Paul C Boutros
  17. School of Computing Sciences, University of East Anglia, Norwich, UK.

    • Christopher Greenman
  18. Department of Molecular Oncology, Barts Cancer Centre, Barts and the London School of Medicine and Dentistry, London, UK.

    • Dan Berney
  19. Laboratory of Reproductive Genomics, Department of Human Genetics, KU Leuven, Leuven, Belgium.

    • Thierry Voet
  20. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.

    • Douglas Easton
  21. Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.

    • Anne Y Warren
  22. Department of Histopathology, University of Liverpool, Liverpool, UK.

    • Christopher S Foster
  23. HCA Pathology Laboratories, London, UK.

    • Christopher S Foster
  24. The Genome Analysis Centre, Norwich, UK.

    • Daniel S Brewer
  25. Department of Surgical Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

    • David E Neal


  1. the ICGC Prostate Group

    A full list of members and affiliations is provided in the Supplementary Note.


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C.S.C., R.E. and D.E.N. are senior principal investigators who designed and coordinated the study. C.S.F. is a senior principal investigator and histopathology lead. D.S.B. and U.M. are senior principal investigators for this project and bioinformatics project coordinators. D.E., A.F. and M.R.S. are senior principal investigators for this project. D.C.W. and P.V.L. had overall responsibility for data analysis. A.Y.W. is a histopathology lead. G.G. performed chromoplexy analysis. L.B.A. analyzed mutational signatures. H.C.W. was a principal investigator for this particular project who also carried out data analysis and tissue collection. A.B. and S.O'M. are coordinators of the DNA mutation–analysis pipeline. C.E.M. was involved in data analysis and formulation of the manuscript structure. P.C., B.K., J.Z., S.N.-Z. and A.G.L. were involved in data analysis and interpretation. N.D., S.E., L. Matthews and S. Merson completed tissue collection and FISH analysis of DNA preparations. N.C., C.G., M.R. and Z.K.-T. carried out data analysis. D.L. performed data validation. J.K. and H.J.L. collected tissue and performed DNA extractions. S.T. obtained patient consent, collected blood and carried out blood DNA preparations. J.C. and R.H. performed FISH analysis. R.M. and T.V. were involved in data interpretation. R.G.B., P.C.B. and M.F. were involved in determining the overall study design. S.C., K.R., D.J., A.M., L.S., J.H., J.T., S. McLaren, L. Mudie, C.H., E.A., O.J., V. Goody, B.R., M.M. and S.G. ran the data mutational analysis pipeline. C.F., C.C., D.B., N.L. and S.H. completed histopathology and tissue collection. C.O., P.K., A.T., C.W., D.N., E.M., T.D., N.C.S. and V. Gnanapragasam were responsible for tissue collection.

Competing interests

R.E. has received educational grants from Illumina and GenProbe (formerly Tepnel), Vista Diagnostics and Janssen Pharmaceuticals, as well as honoraria from Succint Communications for talks on prostate cancer genetics.

Corresponding authors

Correspondence to Colin S Cooper or Rosalind Eeles or David E Neal.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–9, Supplementary Tables 1–3 and Supplementary Note.

Excel files

  1. 1.

    Supplementary Data Set 1

    Copy-number alterations

  2. 2.

    Supplementary Data Set 2

    Substitutions detected

  3. 3.

    Supplementary Data Set 3

    Insertions and deletions detected

  4. 4.

    Supplementary Data Set 4

    Structural variants detected

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