Article | Published:

Divergent clonal selection dominates medulloblastoma at recurrence

Nature volume 529, pages 351357 (21 January 2016) | Download Citation


The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon–driven, functional genomic mouse model of medulloblastoma with ‘humanized’ in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.

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The MAGIC project is financially supported by: Genome Canada, Genome BC, Terry Fox Research Institute, Ontario Institute for Cancer Research, Pediatric Oncology Group Ontario, Funds from ‘The Family of Kathleen Lorette’ and the Clark H. Smith Brain Tumour Centre, Montreal Children’s Hospital Foundation, Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, B.R.A.I.N. Child, and BC Childhood Cancer Parents Association. M.D.T. is also supported by a Stand Up To Cancer St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113). Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. M.D.T. is supported by The Canadian Cancer Society Research Institute, The Garron Family Chair in Childhood Cancer Research, and grants from the Cure Search for Children’s Cancer Foundation, the National Institutes of Health (R01CA148699 R01CA159859), The Pediatric Brain Tumour Foundation, The Terry Fox Research Institute, Brainchild and The McLaughlin Centre at the University of Toronto. M.D.T. is also supported by the Swifty Foundation. L.G. was supported by the Davis M. Ferguson Memorial Fund at ABTA. Alex’s Lemonade Stand Young Investigator Award supported V.R. This study was conducted with the support of the Ontario Institute for Cancer Research through funding provided by the Government of Ontario. This work was also supported by a Program Project Grant from the Terry Fox Research Institute, and a Grand Challenge Award from CureSearch for Children’s Cancer. Additionally, this work was supported by the PedBrain Tumour Project contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (BMBF, grants 01KU1201A, MedSys 0315416C and NGFNplus 01GS0883). Funding by the German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung) to S.M.P., G.F. and T.P. The study was also financed by the Hungarian Brain Research Program Grant No. KTIA_13_NAP-A-V/3. and NAP-A-II/7. A.K. was supported by the János Bolyai scholarship of the Hungarian Academy of Sciences. E.G.V.M. was supported by NIH R01 grants CA163722 and NS096236, and St. Baldrick’s and Cure Childhood Cancer Foundations. We would like to acknowledge R. P. Hill (Ontario Cancer Institute), the Labatt Brain Tumour Research Centre Tumour and Tissue Repository, which is supported by B.R.A.I.N. Child and Megan’s Walk. M.R. is supported by a fellowship from the Dr. Mildred Scheel Foundation for Cancer Research/German Cancer Aid. F.M.G.C. is supported by the Stephen Buttrum Brain Tumour Research Fellowship, granted by Brain Tumour Foundation of Canada. V.R. is supported by a CIHR fellowship and an Alberta Innovates-Health Solutions Clinical Fellowship. We would like to thank the Toronto Centre for Phenogenomics for animal housing and veterinary support, and the Preclinical Core II and animal research facility at STTARR (Spatiotemporal Targeting and Amplification of Radiation Response) in Toronto for assistance with CT-guided radiation experiments. We would like to thank Z. Wang for technical help with IHC, S. Archer for technical writing and C. Smith for artwork.

Author information

Author notes

    • A. Sorana Morrissy
    •  & Livia Garzia

    These authors contributed equally to this work.

    • Marco A. Marra
    •  & Michael D. Taylor

    These authors jointly supervised this work.


  1. Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada

    • A. Sorana Morrissy
    • , Livia Garzia
    • , David J. H. Shih
    • , Xi Huang
    • , Patryk Skowron
    • , Florence M. G. Cavalli
    • , Vijay Ramaswamy
    • , Laura K. Donovan
    • , Xin Wang
    • , Betty Luu
    • , Kory Zayne
    • , Hamza Farooq
    • , Noriyuki Kijima
    • , Borja L. Holgado
    • , John J. Y. Lee
    • , Stuart Matan-Lithwick
    • , Jessica Liu
    • , Stephen C. Mack
    • , Alex Manno
    • , K. A. Michealraj
    • , Carolina Nor
    • , John Peacock
    • , Lei Qin
    • , Adi Rolider
    • , Yuan Y. Thompson
    • , Xiaochong Wu
    •  & Michael D. Taylor
  2. The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada

    • A. Sorana Morrissy
    • , Livia Garzia
    • , David J. H. Shih
    • , Patryk Skowron
    • , Florence M. G. Cavalli
    • , Vijay Ramaswamy
    • , Laura K. Donovan
    • , Xin Wang
    • , Betty Luu
    • , Kory Zayne
    • , Hamza Farooq
    • , Noriyuki Kijima
    • , Borja L. Holgado
    • , John J. Y. Lee
    • , Stuart Matan-Lithwick
    • , Jessica Liu
    • , Stephen C. Mack
    • , Alex Manno
    • , K. A. Michealraj
    • , Carolina Nor
    • , John Peacock
    • , Lei Qin
    • , Juri Reimand
    • , Adi Rolider
    • , Yuan Y. Thompson
    • , Xiaochong Wu
    • , Uri Tabori
    • , Cynthia E. Hawkins
    • , Peter Dirks
    • , Eric Bouffet
    • , James T. Rutka
    •  & Michael D. Taylor
  3. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5G 0A4, Canada

    • David J. H. Shih
    • , Patryk Skowron
    • , Vijay Ramaswamy
    • , Xin Wang
    • , John J. Y. Lee
    • , John Peacock
    • , Yuan Y. Thompson
    • , James T. Rutka
    •  & Michael D. Taylor
  4. The Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada

    • Scott Zuyderduyn
    • , Juri Reimand
    •  & Gary D. Bader
  5. Department of Pediatric Oncology, Hematology, and Clinical Immunology, University Hospital Düsseldorf, M5S 3E1, Germany

    • Marc Remke
  6. Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario M5S 3E1, Canada

    • Vijay Ramaswamy
    • , Caitlin Hoffman
    • , Peter Dirks
    • , James T. Rutka
    •  & Michael D. Taylor
  7. Department of Radiation Oncology, University of Toronto, Toronto, Ontario M5G 2M9, Canada

    • Patricia E. Lindsay
  8. Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario M5G 2M9, Canada

    • Patricia E. Lindsay
    •  & Salomeh Jelveh
  9. Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia V5Z 4S6, Canada

    • Yisu Li
    • , Chelsea Mayoh
    • , Nina Thiessen
    • , Eloi Mercier
    • , Karen L. Mungall
    • , Yusanne Ma
    • , Kane Tse
    • , Thomas Zeng
    • , Adrian Ally
    • , Mikhail Bilenky
    • , Yaron S. N. Butterfield
    • , Rebecca Carlsen
    • , Young Cheng
    • , Eric Chuah
    • , Richard D. Corbett
    • , Noreen Dhalla
    • , An He
    • , Darlene Lee
    • , Haiyan I. Li
    • , William Long
    • , Michael Mayo
    • , Patrick Plettner
    • , Jenny Q. Qian
    • , Jacqueline E. Schein
    • , Angela Tam
    • , Tina Wong
    • , Inanc Birol
    • , Yongjun Zhao
    • , Andrew J. Mungall
    • , Richard A. Moore
    • , Steven J. M. Jones
    •  & Marco A. Marra
  10. Department of Molecular Oncology, BC Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada

    • Karey Shumansky
    • , Andrew J. L. Roth
    •  & Sohrab Shah
  11. Center for Stem Cell & Regenerative Medicine, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA

    • Stephen C. Mack
  12. Clinical Genomics Research Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario 44195, Canada

    • Trevor Pugh
  13. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada

    • Inanc Birol
    • , Steven J. M. Jones
    •  & Marco A. Marra
  14. School of Computing Science, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada

    • Inanc Birol
  15. Division of Neurosurgery, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon 1649-035, Portugal

    • Claudia C. Faria
  16. Divison of Pathology, Centro Hospitalar Lisboa Norte, Hospital de Santa Maria, Lisbon 1649-035, Portugal

    • José Pimentel
  17. Unidade de Neuro-Oncologia Pediátrica, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisbon 1099-023, Portugal

    • Sofia Nunes
  18. Departments of Oncology and Neuro-Oncology, University Children’s Hospital of Zurich, Zurich 8032, Switzerland

    • Tarek Shalaby
    •  & Michael Grotzer
  19. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224, USA

    • Ian F. Pollack
  20. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA

    • Ronald L. Hamilton
  21. Brain Tumor Program, Children's Cancer Center and Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA

    • Xiao-Nan Li
  22. Pediatric Hematology-Oncology, Children’s Hospitals and Clinics of Minnesota, Minneapolis, Minnesota 55404, USA

    • Anne E. Bendel
  23. Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah 84132, USA

    • Daniel W. Fults
  24. A I duPont Hospital for Children, Wilmington, Delaware 19803, USA

    • Andrew W. Walter
  25. Department of Neurosurgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan

    • Toshihiro Kumabe
  26. Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai 980-8574, Japan

    • Teiji Tominaga
  27. Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK

    • V. Peter Collins
  28. Departments of Neurosurgery, Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA

    • Yoon-Jae Cho
  29. Departments of Pediatrics, Cell & Developmental Biology, Weill Medical College of Cornell University, New York, New York 10065, USA

    • David Lyden
  30. Department of Neurosurgery, NYU Langone Medical Center, New York, New York 10016, USA

    • Jeffrey H. Wisoff
  31. Department of Pediatrics, Division of Pediatric Hematology, Oncology, and Stem Cell Transplantation, Columbia University, New York, New York 10032, USA

    • James H. Garvin
  32. Department of Pediatrics-Hematology and Oncology, Rainbow Babies & Children’s Hospital and Department of Pediatrics-Hematology and Oncology, Case Western Reserve, Cleveland, Ohio 44106, USA

    • Duncan S. Stearns
  33. Pediatric Neurosurgery, Catholic University Medical School, Rome 00198, Italy

    • Luca Massimi
  34. Center for Neuropathology, Ludwig-Maximilians-Universität, Munich 81377, Germany

    • Ulrich Schüller
  35. Department of Pediatric Oncology, School of Medicine, Masaryk University, Brno 625 00, Czech Republic

    • Jaroslav Sterba
    •  & Karel Zitterbart
  36. AP-HP, Department of Neurosurgery, Necker-Enfants Malades Hospital, Université René Descartes, Paris 75743, France

    • Stephanie Puget
  37. Signaling in Development and Brain Tumors, CNRS UMR 3347 / INSERM U1021, Institut Curie, Paris Cedex 5 91405, France

    • Olivier Ayrault
  38. Division of Hematology/Oncology, British Columbia Children’s Hospital, Vancouver, British Columbia V6H 3V4, Canada

    • Sandra E. Dunn
  39. Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, Universidade de São Paulo, Brazil, Rebeirao Preto, São Paulo 14049-900, Brazil

    • Daniela P. C. Tirapelli
    •  & Carlos G. Carlotti
  40. Kolling Institute of Medical Research, The University of Sydney, Sydney, New South Wales 2065, Australia

    • Helen Wheeler
  41. Queensland Children's Medical Research Institute, Children’s Health Queensland, Brisbane, Queensland 4029, Australia

    • Andrew R. Hallahan
    •  & Wendy Ingram
  42. Division of Oncology, Children’s Health Queensland, Brisbane, Queensland 4029, Australia

    • Andrew R. Hallahan
  43. UQ Child Health Research Centre, The University of Queensland, Brisbane 4029, Australia

    • Wendy Ingram
  44. Pediatric Neuro-Oncology Program, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia 30307, USA

    • Tobey J. MacDonald
  45. Department of Neurosurgery, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA

    • Jeffrey J. Olson
  46. Department of Hematology & Medical Oncology, School of Medicine and Winship Cancer Institute, Emory University, Atlanta, Georgia 30322, USA

    • Erwin G. Van Meir
  47. Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children’s Hospital, Seoul 30322, South Korea

    • Ji-Yeoun Lee
    • , Kyu-Chang Wang
    • , Seung-Ki Kim
    •  & Byung-Kyu Cho
  48. Institute for Neuropathology, University of Bonn D-53105, Germany

    • Torsten Pietsch
  49. Children’s University Hospital of Essen D-45147, Germany

    • Gudrun Fleischhack
    •  & Stephan Tippelt
  50. Department of Neurosurgery, University of Ulsan, Asan Medical Center, Seoul 05505, South Korea

    • Young Shin Ra
  51. Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE1 4LP, UK

    • Simon Bailey
    • , Janet C. Lindsey
    •  & Steven C. Clifford
  52. Departments of Pathology, Ophthalmology and Oncology, John Hopkins University School of Medicine, Baltimore, Maryland 21205, USA

    • Charles G. Eberhart
  53. Department of Neurology, Vanderbilt Medical Center, Nashville, Tennessee 37232-8550, USA

    • Michael K. Cooper
  54. Department of Neurology, Children’s National Medical Center, Washington DC 20010-2970, USA

    • Roger J. Packer
  55. Fondazione IRCCS Istituto Nazionale Tumori, Milan 20133, Italy

    • Maura Massimino
  56. U.O. Neurochirurgia, Istituto Giannina Gaslini, Genova 16147, Italy

    • Maria Luisa Garre
  57. Department of Haematology & Oncology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada

    • Ute Bartels
    • , Uri Tabori
    • , Eric Bouffet
    •  & David Malkin
  58. Division of Pathology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada

    • Cynthia E. Hawkins
  59. Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA

    • Robert J. Wechsler-Reya
  60. Departments of Pediatrics, Neurology and Neurosurgery, University of California San Francisco, San Francisco, California 94158, USA

    • William A. Weiss
  61. School of Pharmacology, University of Wisconsin, Madison, Wisconsin 53715, USA

    • Lara S. Collier
  62. Molecular & Cellular Biology Program, University of Iowa, Iowa City, Iowa 52242, USA

    • Adam J. Dupuy
  63. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany

    • Andrey Korshunov
  64. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany

    • David T. W. Jones
    • , Marcel Kool
    • , Paul A. Northcott
    •  & Stefan M. Pfister
  65. Department of Pediatric Oncology, University Hospital Heidelberg, Heidelberg 69120, Germany

    • Stefan M. Pfister
  66. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA

    • David A. Largaespada
  67. Division of Hematology/Oncology, McGill University, Montreal, Quebec H2W 1S6., Canada

    • Nada Jabado
  68. McLaughlin Centre and Department of Molecular Genetics, Banting and Best Department of Medical Research and Samuel Lunenfeld Research Institute at Mount Sinai Hospital, University of Toronto, Toronto, Ontario M5G 1L7, Canada

    • Gary D. Bader
  69. Department of Molecular Biology & Biochemistry, Simon Fraser University, Burnaby, British Columbia M5G 1L7, Canada

    • Steven J. M. Jones
  70. Department of Pediatrics, University of Toronto, Toronto, Ontario M5G 1X8, Canada

    • David Malkin


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A.S.M., L.G., and M.D.T. led the study. L.G. planned and carried out in vivo and in vitro experiments and analyses, and performed a subset of bioinformatic analyses. A.S.M. supervised the RNA-seq and WGS experiments, led and executed bioinformatic analyses. D.J.H.S. performed bioinformatics analysis of mutation signatures. S.Z. developed and implemented the computational method of finding initiating events in mouse tumours. X.H. developed the Drosophila brain tumour model and performed imaging of Drosophila brains. P.S. assisted with mouse library preparation and bioinformatics analysis. M.R. and V.R. performed bioinformatics analyses on DYNC1H1 and 14q loss. F.M.G.C. generated visualizations of structural rearrangements. P.E.L. and S.J. developed the radiotherapy schedule for the mouse model and designed the custom made collimators, beds, and stages for mouse CSI. K.Z. assisted with library preparation. B.L. extracted nucleic acids, managed the biobanking, and maintained the patient database. N.T., Y.M., and K.L.M. supervised bioinformatics analyses at the Genome Sciences Center, including sequence alignment, copy number analysis, and SNV and structural variant calling. Y.L., C.M. and E.M. performed bioinformatics analysis of human sequencing and deep-sequencing data. K.T. and T.Z. supervised and implemented the targeted deep-sequencing work. K.S. performed PyClone analysis. A.J.L.R. and S.S. designed and implemented PyClone, and supervised its use. H.F., S.M-L., J.R., and T.P. assisted with bioinformatic analyses. J.L., and L.Q., assisted with animal care, and N.K., B.L.H., J.J.Y.L., L.K.D., Xin W., S.C.M., A.M., K.A.M., C.N., John P., A.R., and Y.Y.T. provided technical support. Xiaochong W. generated the transgenic mouse model and offered technical advice. A.A., M.B., Y.S.N.B., R.C., Y.C., E.C., R.C., N.D., A.H., D.L., H.I.L., W.L., M.M., P.P., J.Q.Q., J.E.S., A.T., T.W., I.B., and Y.Z., led and performed RNA-seq and WGS library preparation and sequencing experiments and performed data analyses. A.K., D.T.W.J., M.K., P.A.N., and S.M.P. at DKFZ performed the sequencing of four patients’ sets. C.C.F., José P., S.N., T.S., M.G., I.F.P., R.L.H., X.-N.Li., A.E.B., D.W.F., A.W.W., T.K., T.T., V.P.C., Y.-J.C., C.H., D.L., J.H.W., J.H.G. Jr, D.S.S., L.M., U.S., J.S., K.Z., S.P., O.A., S.E.D., D.P.C.T., C.G.C., H.W., A.R.H., W.I., T.J.M., J.J.O., E.G.V.M., J.-Y.L., K.-C.W., S.-K.K., B.-K.C., Y.S.R., S.B., J.C.L., S.C.C., C.G.E., M.K.C., R.J.P., M.M., M.L.G., N.J., and S.M.P. obtained the patient samples and clinical details that made the study possible. T.P., G.F., S.T., U.B., U.T., C.E.H., P.D., E.B., J.T.R., R.J.W.-R., W.A.W., L.S.C., A.J.D., A.K., D.T.W.J., M.K., P.A.N., S.M.P., D.A.L., A.J.M., R.A.M., N.J., G.D.B., S.J.M.J., and D.M. provided valuable input regarding study design, data analysis, and interpretation of results. A.S.M., L.G., M.R., S.Z., G.D.B., M.A.M. and M.D.T. wrote the manuscript. M.A.M. and M.D.T. provided financial and technical infrastructure and oversaw the study. M.A.M. and M.D.T. are joint senior authors and project co-leaders.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Marco A. Marra or Michael D. Taylor.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains full legends for Supplementary Tables 1-4, Supplementary Text and Data – see contents page for full details.

Excel files

  1. 1.

    Supplementary Table 1

    This file contains driver genes prediction in mouse primary and recurrent tumours – see Supplementary Information document for full legend.

  2. 2.

    Supplementary Table 2

    This table contains patient information, analyses summary, and associated clinical data - see Supplementary Information document for full legend.

  3. 3.

    Supplementary Table 3

    This table contains positions verified by deep sequencing – see Supplementary Information document for full legend.

  4. 4.

    Supplementary Table 4

    This table contains prognostic implications of chr14 loss in Shh MB – see Supplementary Information document for full legend.

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