Letter | Published:

Spatial heterogeneity in medulloblastoma

Nature Genetics volume 49, pages 780788 (2017) | Download Citation

Abstract

Spatial heterogeneity of transcriptional and genetic markers between physically isolated biopsies of a single tumor poses major barriers to the identification of biomarkers and the development of targeted therapies that will be effective against the entire tumor. We analyzed the spatial heterogeneity of multiregional biopsies from 35 patients, using a combination of transcriptomic and genomic profiles. Medulloblastomas (MBs), but not high-grade gliomas (HGGs), demonstrated spatially homogeneous transcriptomes, which allowed for accurate subgrouping of tumors from a single biopsy. Conversely, somatic mutations that affect genes suitable for targeted therapeutics demonstrated high levels of spatial heterogeneity in MB, malignant glioma, and renal cell carcinoma (RCC). Actionable targets found in a single MB biopsy were seldom clonal across the entire tumor, which brings the efficacy of monotherapies against a single target into question. Clinical trials of targeted therapies for MB should first ensure the spatially ubiquitous nature of the target mutation.

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Acknowledgements

The MAGIC project (M.D.T. and M.A.M.) 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, M.D.T.'s Garron Family Endowment, and the BC Childhood Cancer Parents Association. M.D.T. is 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 also supported by The Garron Family Chair in Childhood Cancer Research, and grants from the Cure Search Foundation, the US National Institutes of Health (R01CA148699 and R01CA159859), The Pediatric Brain Tumor Foundation, The Terry Fox Research Institute, and Brainchild. This study was conducted with the support of the Ontario Institute for Cancer Research through funding provided by the Government of Ontario, as well as The Brain Tumour Foundation of Canada Impact Grant of the Canadian Cancer Society and Brain Canada with the financial assistance of Health Canada (grant 703202 to M.D.T.). This work was also supported by a Program Project Grant from the Terry Fox Research Institute (to M.D.T.), a Grand Challenge Award from CureSearch for Children's Cancer (to M.D.T.), and the PedBrain Tumor 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 and MedSys 0315416C to S.M.P. and P.L.). We acknowledge 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.D.T.). M.A.M. acknowledges support from the Canadian Institutes of Health Research (CIHR; FDN-143288). 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 the Brain Tumour Foundation of Canada. V.R. is supported by a CIHR fellowship and an Alberta Innovates–Health Solutions Clinical Fellowship. For technical support and expertise in next-generation sequencing efforts, we thank The Centre for Applied Genomics (Toronto, Ontario, Canada). We thank S. Archer for technical writing, and C. Smith for artwork.

Author information

Author notes

    • A Sorana Morrissy
    • , Florence M G Cavalli
    •  & Marc Remke

    These authors contributed equally to this work.

Affiliations

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

    • A Sorana Morrissy
    • , Florence M G Cavalli
    • , Marc Remke
    • , Vijay Ramaswamy
    • , David J H Shih
    • , Borja L Holgado
    • , Hamza Farooq
    • , Laura K Donovan
    • , Livia Garzia
    • , Maria Vladoiu
    • , Betty Luu
    • , Xiaochong Wu
    • , Craig Daniels
    • , Yuan Yao Thompson
    • , John Peacock
    • , Xin Wang
    • , Stephen C Mack
    • , Sunit Das
    •  & Michael D Taylor
  2. The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • A Sorana Morrissy
    • , Florence M G Cavalli
    • , Marc Remke
    • , Vijay Ramaswamy
    • , David J H Shih
    • , Borja L Holgado
    • , Hamza Farooq
    • , Laura K Donovan
    • , Livia Garzia
    • , Jonathon Torchia
    • , Diana M Merino
    • , Maria Vladoiu
    • , Betty Luu
    • , Xiaochong Wu
    • , Yuan Yao Thompson
    • , John Peacock
    • , Xin Wang
    • , Stephen C Mack
    • , James Loukides
    • , Cynthia E Hawkins
    • , Uri Tabori
    • , Peter Dirks
    • , Annie Huang
    • , Eric Bouffet
    • , James T Rutka
    • , Sunit Das
    •  & Michael D Taylor
  3. Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.

    • Marc Remke
    •  & Daniel Picard
  4. Department of Neuropathology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany.

    • Marc Remke
    •  & Daniel Picard
  5. Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Düsseldorf, Germany.

    • Marc Remke
    •  & Daniel Picard
  6. Division of Haematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Vijay Ramaswamy
    • , Jonathon Torchia
    • , Diana M Merino
    • , Uri Tabori
    • , Annie Huang
    • , Eric Bouffet
    •  & David Malkin
  7. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

    • David J H Shih
    • , Hamza Farooq
    • , Jonathon Torchia
    • , Yuan Yao Thompson
    • , John Peacock
    • , Xin Wang
    • , Stephen C Mack
    • , James T Rutka
    •  & Michael D Taylor
  8. Cancer Research Program, McGill University Health Centre Research Institute, Montreal, Quebec, Canada.

    • Livia Garzia
  9. MacFeeters-Hamilton Brain Tumour Centre, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

    • Sameer Agnihotri
  10. Division of Neurosurgery, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Erin N Kiehna
    • , Peter Dirks
    •  & James T Rutka
  11. Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada.

    • Eloi Mercier
    • , Chelsea Mayoh
    • , Nina Thiessen
    • , Yisu Li
    • , Jacqueline E Schein
    • , Darlene Lee
    • , Rebecca Carlsen
    • , Michael Mayo
    • , Kane Tse
    • , Angela Tam
    • , Noreen Dhalla
    • , Adrian Ally
    • , Eric Chuah
    • , Young Cheng
    • , Patrick Plettner
    • , Haiyan I Li
    • , Richard D Corbett
    • , Tina Wong
    • , William Long
    • , Yusanne Ma
    • , Richard A Moore
    • , Andrew J Mungall
    • , Steven J M Jones
    •  & Marco A Marra
  12. Departments of Pediatrics and Human Genetics, McGill University, Montreal, Quebec, Canada.

    • Simon Papillon-Cavanagh
    • , Hamid Nikbakht
    •  & Tenzin Gayden
  13. Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Diana M Merino
  14. Cancer Research UK London Research Institute, London, UK.

    • Stuart Horswell
  15. Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Volker Hovestadt
    •  & Peter Lichter
  16. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Paul A Northcott
    • , David T W Jones
    • , Marcel Kool
    •  & Stefan M Pfister
  17. Informatics and Biocomputing, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.

    • Jüri Reimand
  18. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.

    • Jüri Reimand
  19. The Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.

    • Jüri Reimand
    •  & Gary D Bader
  20. Department of Pathology, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.

    • Steffen Albrecht
  21. Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.

    • Adam M Fontebasso
    • , Jacek Majewski
    •  & Nada Jabado
  22. Division of Pathology, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Pawel Buczkowicz
    •  & Cynthia E Hawkins
  23. Division of Pediatric Oncology, Children's National Medical Center, Washington, DC, USA.

    • Brian R Rood
  24. Division of Pediatric Neuro-Surgery, Children's National Medical Center, Washington, DC, USA.

    • John S Myseros
  25. Department of Neurology, Children's National Medical Center, Washington, DC, USA.

    • Roger J Packer
  26. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Andrey Korshunov
  27. German Cancer Consortium (DKTK), Heidelberg, Germany.

    • Peter Lichter
    •  & Stefan M Pfister
  28. Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, University Hospital Heidelberg, Heidelberg, Germany.

    • Stefan M Pfister
  29. Institute of Neuropathology, University Medical Center, Hamburg-Eppendorf, Germany.

    • Ulrich Schüller
  30. Research Institute Children's Cancer Center, Hamburg, Germany.

    • Ulrich Schüller
  31. Pediatric Hematology and Oncology, University Medical Center, Hamburg-Eppendorf, Germany.

    • Ulrich Schüller
  32. Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, London, UK.

    • Charles Swanton
  33. Cancer Research UK Lung Cancer Centre of Excellence, University College London, London, UK.

    • Charles Swanton
  34. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.

    • Steven J M Jones
    •  & Marco A Marra
  35. Department of Molecular Biology & Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada.

    • Steven J M Jones
  36. Division of Neurosurgery, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.

    • Sunit Das

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Contributions

A.S.M., F.M.G.C., M.R., M.D.T., and M.A.M. led the study and wrote the manuscript. A.S.M. and F.M.G.C. designed, supervised, and performed bioinformatic analyses. M.R. led the collection of samples and data generation, and performed bioinformatic analyses. B.L. extracted nucleic acids, managed biobanking, and maintained the patient database. S.H., A.M.F., B.L.H., C.D., D.J.H.S., D.M.M., D.P., D.T.W.J., E.N.K., H.F., J.M., J.P., J.R., J.T., L.G., L.K.D., M.V., P.A.N., S. Agnihotri, S. Albrecht, S.C.M., S.P.-C., V.H., V.R., X. Wu, X. Wang, and Y.Y.T. provided technical and bioinformatic support. A.A., A.T., C.M., D.L., E.C., E.M., H.I.L., J.E.S., K.T., M.M., N.D., P.P., R.C., R.D.C., T.W., W.L., Y.C., and Y.L. led and performed RNA-seq and whole-genome sequencing library preparation and sequencing experiments, and performed data analyses. N.T. and Y.M. supervised bioinformatic analyses at the Genome Sciences Center. H.N. and T.G. performed whole-exome sequencing library preparation and sequencing experiments, and performed data analyses. B.R.R., C.S., C.E.H., J.L., J.S.M., N.J., P.B., R.J.P., S.D., and U.S. provided the patient samples and clinical details that made the study possible. A.H., A.J.M., A.K., D.M., E.B., G.D.B., J.T.R., M.K., P.D., P.L., R.A.M., S.J.M.J., S.M.P., and U.T. provided valuable input regarding study design, data analysis, and interpretation of results. M.D.T. and M.A.M. provided financial and technical infrastructure and oversaw the study, and served as 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.

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DOI

https://doi.org/10.1038/ng.3838

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