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

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• 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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Acknowledgements

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.

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Author notes

1. 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 and David E Neal: These authors contributed equally to this work.
2. Colin S Cooper, Rosalind Eeles, Christopher S Foster, Ultan McDermott, Daniel S Brewer and David E Neal: These authors jointly supervised this work.

Authors and Affiliations

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. Department of Human Genetics, Human Genome Laboratory, 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. Department of Human Genetics, Laboratory of Reproductive Genomics, KU Leuven, Leuven, Belgium
    Thierry Voet
20. Department of Oncology, Centre for Cancer Genetic Epidemiology, 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

Authors

1. Colin S Cooper
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2. Rosalind Eeles
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3. David C Wedge
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4. Peter Van Loo
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5. Gunes Gundem
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6. Ludmil B Alexandrov
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7. Barbara Kremeyer
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8. Adam Butler
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9. Andrew G Lynch
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10. Niedzica Camacho
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11. Charlie E Massie
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12. Jonathan Kay
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13. Hayley J Luxton
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14. Sandra Edwards
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15. Zsofia Kote-Jarai
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16. Nening Dennis
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17. Sue Merson
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18. Daniel Leongamornlert
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19. Jorge Zamora
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20. Cathy Corbishley
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21. Sarah Thomas
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22. Serena Nik-Zainal
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23. Manasa Ramakrishna
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24. Sarah O'Meara
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25. Lucy Matthews
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26. Jeremy Clark
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27. Rachel Hurst
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28. Richard Mithen
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29. Robert G Bristow
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30. Paul C Boutros
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31. Michael Fraser
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32. Susanna Cooke
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33. Keiran Raine
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34. David Jones
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35. Andrew Menzies
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36. Lucy Stebbings
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37. Jon Hinton
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38. Jon Teague
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39. Stuart McLaren
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40. Laura Mudie
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41. Claire Hardy
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42. Elizabeth Anderson
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43. Olivia Joseph
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44. Victoria Goody
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45. Ben Robinson
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46. Mark Maddison
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47. Stephen Gamble
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48. Christopher Greenman
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49. Dan Berney
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50. Steven Hazell
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51. Naomi Livni
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52. Cyril Fisher
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53. Christopher Ogden
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54. Pardeep Kumar
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55. Alan Thompson
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56. Christopher Woodhouse
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57. David Nicol
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58. Erik Mayer
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59. Tim Dudderidge
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60. Nimish C Shah
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61. Vincent Gnanapragasam
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62. Thierry Voet
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63. Peter Campbell
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64. Andrew Futreal
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65. Douglas Easton
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66. Anne Y Warren
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67. Christopher S Foster
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68. Michael R Stratton
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69. Hayley C Whitaker
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70. Ultan McDermott
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71. Daniel S Brewer
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72. David E Neal
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Consortia

the ICGC Prostate Group

Contributions

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.

Corresponding authors

Correspondence toColin S Cooper, Rosalind Eeles or David E Neal.

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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.

Additional information

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

Integrated supplementary information

Supplementary Figure 1 Detection of ERG breakpoints in Case 7.

The top (a) and middle (b) panels are identical to those shown panels b and c of Fig. 1. This figure additionally shows the FISH images (c) that demonstrate the positions of breaks G, H and J (see Fig. 3 for the precise positions of breaks G and H). FISH was carried out exactly as described previously1. “Split” denotes that 5’ and 3’ ERG signals were separated but retained in the cell. “Del” indicates that 5’ ERG signals were lost from the cell, while 3’ ERG signals were retained.

Supplementary Figure 2 Three dimensional reconstructions of prostates from Patient 6, Patient 7, and Patient 8.

Showing the position of the cancer (purple shading) and the locations where samples were selected (labeled black circles) for DNA sequencing. Reconstruction was based on examination of H&E stained sections slices as indicated. Anterior prostate is at the bottom.

Supplementary Figure 3 Mutations and clonal expansions in morphologically normal tissue.

a, Summary of numbers of mutation types. b, Density plots showing the posterior distribution of the fraction of cells bearing a mutation. The fraction of cells is modeled using a previously described Bayesian Dirichlet process2. The median density is indicated by the purple line and 95% confidence intervals by the blue region. The grey histogram shows the observed frequency density of mutations as a function of the fraction of cells bearing the mutation. The y-axis is the probability density. Mutations were present in 10% of cells in Case 8 (not shown).

Supplementary Figure 4 Phylogeny based on copy number alterations alone.

Copy number alterations were detected by the Battenberg algorithm2. Each line is associated with a clone from a particular sample. The length of each line is for ease of visualisation only. The thickness of a line is proportional to its clonal representation.

Supplementary Figure 6 Further examples of 2D density plots showing the posterior distribution of the fraction of cells bearing a substitution in two samples.

The fraction of cells is modeled using Bayesian Dirichlet processes. From these plots it can be seen which samples share shared clonal substitutions when there is a peak at (1,1) e.g. 6_T1/6_T2; branched substitutions when there is only peaks along the axes e.g. 7_T2/7_T3 with peaks at (0,1) and (1,0); and samples that contain a sub-clone. An example of samples with a sub clone are 7_T2/7_T5 that has a peak at (0,0.72), which represents subclonal substitutions in 72% of cells in 7_T5 that have occurred only in this sample, after divergence from the other samples. Similarly, 8_T1/8_T3 has a peak at (0.54,0), representing subclonal mutations in 54% of cells in T1 only.

Supplementary Figure 7 Convergent evolution of 8p loss.

A plot showing the B-allele frequency (BAF) of segments of copy number variation detected by the battenberg algorithm on chromosome 8p. Segments showing no variation will have a BAF of 0.5. The majority of samples apart from the adjacent morphologically normal samples show a deletion at 8p. 8p deletions are at different positions and lengths in different tumors samples from the same patient showing convergent evolution. BAF values vary as a result of differing tumor content in each sample, with higher cellularity samples having more divergent BAF values in aberrant regions.

Supplementary Figure 8 Rainfall plot.

We identified localised clusters of hypermutation, a recently phenomenon termed kataegis, using a previously described algorithm. As in previously observed kataegis events, all clusters were constituted of C>T or a mixture of C>T and C>G mutations and appear to have occurred on a single strand of DNA, consistent with the operation of an APOBEC enzyme. All kataegis events were found only in one clone from each patient suggesting that it is not an initiating event. The horizontal axis illustrates the genomic coordinates of the mutations. The vertical axis plots the distance between mutations. The kataegis events in 6_T3 were both within 350bp of a rearrangement breakpoint. In 7_T2 the kataegis mutations occur on 2 chromosome copies indicating that they occurred before a whole genome duplication event, in 6_T3 the kataegis mutations are subclonal, indicating a late event, while the other two kataegis events occur clonally on one chromosome copy.

Supplementary Figure 9 Chromoplexy analysis of rearrangement breakpoints.

It was recently shown that ~40% of somatic rearrangements in prostate cancer were found in a complex series of events, called chromoplexy, that are chained together by virtue of either the proximity of their breakpoints or the existence of a 'deletion bridge' in between them5. In our multifocal prostate cancers, we identified 14 unique chromoplexy events using the ChainFinder algorithm. The oncogenic _TMRSS2_-ERG fusion occurred as part of a chromoplexy event in some (6_T3, 6_T4, 7_T1/T2 and 8_T1/T2) but not all tumour foci. In patients 6 and 7, we identified multiple chromoplexy events in distinct tumour cell lineages. Circos plots are shown for each sample on the corresponding branch of the phylogenetic tree. The outer rings in the circus plot provides a genomic view of the copy number changes (blue logR<-0.1, red lowR>0.1 and grey otherwise.) Rearrangement events are annotated with non-grey colours if they are found to be in chromoplexy events by the algorithm and grey otherwise.

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Cooper, C., Eeles, R., Wedge, D. et al. Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue.Nat Genet 47, 367–372 (2015). https://doi.org/10.1038/ng.3221

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• Received: 29 September 2014
• Accepted: 21 January 2015
• Published: 02 March 2015
• Issue Date: April 2015
• DOI: https://doi.org/10.1038/ng.3221