Abstract

Diffuse intrinsic pontine glioma (DIPG) is a fatal brain cancer that arises in the brainstem of children, with no effective treatment and near 100% fatality. The failure of most therapies can be attributed to the delicate location of these tumors and to the selection of therapies on the basis of assumptions that DIPGs are molecularly similar to adult disease. Recent studies have unraveled the unique genetic makeup of this brain cancer, with nearly 80% found to harbor a p.Lys27Met histone H3.3 or p.Lys27Met histone H3.1 alteration. However, DIPGs are still thought of as one disease, with limited understanding of the genetic drivers of these tumors. To understand what drives DIPGs, we integrated whole-genome sequencing with methylation, expression and copy number profiling, discovering that DIPGs comprise three molecularly distinct subgroups (H3-K27M, silent and MYCN) and uncovering a new recurrent activating mutation affecting the activin receptor gene ACVR1 in 20% of DIPGs. Mutations in ACVR1 were constitutively activating, leading to SMAD phosphorylation and increased expression of the downstream activin signaling targets ID1 and ID2. Our results highlight distinct molecular subgroups and novel therapeutic targets for this incurable pediatric cancer.

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Acknowledgements

We would like to thank all of the patients and families for donating tissue for this research. This work was supported by the Canadian Institutes of Health Research (CIHR, MOP 115004) and was funded in part by a Genome Canada/CIHR grant (cofunding from Genome BC, Génome Québec, CIHR-ICR (Institute for Cancer Research) and C17, through the Genome Canada/CIHR joint ATID Competition (project title: The Canadian Paediatric Cancer Genome Consortium (CPCGC): Translating Next-Generation Sequencing Technologies into Improved Therapies for High-Risk Childhood Cancer)). P.B. is a recipient of a CIHR Doctoral Frederick Banting and Charles Best Canada Graduate Scholarships award. O.B. is a Damon Runyon Clinical Investigator and is supported by the US Department of Defense and the Pediatric Brain Tumor Foundation. C.J., A. Mackay and K.R.T. acknowledge National Health Service (NHS) funding to the Biomedical Research Centre and support from the Stavros Niarchos Foundation. Sample collection for M.A.K. and D.Z. was supported in part by grant UL1TR000038 from the National Center for Research Resources, US National Institutes of Health and by grant 5P30CA016087-32 from the National Cancer Institute.

Author information

Author notes

    • Pawel Buczkowicz
    •  & Christine Hoeman

    These authors contributed equally to this work.

    • Oren Becher
    •  & Cynthia Hawkins

    These authors jointly directed this work.

Affiliations

  1. Division of Pathology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

    • Pawel Buczkowicz
    •  & Cynthia Hawkins
  2. Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Pawel Buczkowicz
    • , Patricia Rakopoulos
    • , Sanja Pajovic
    • , Andrew Morrison
    • , Jennifer Zuccaro
    • , Sameer Agnihotri
    • , Scott Ryall
    • , Mark Barszczyk
    • , Yevgen Chornenkyy
    • , Pedro Castelo-Branco
    • , Joshua Mangerel
    • , Uri Tabori
    • , King Ching Ho
    • , Annie Huang
    •  & Cynthia Hawkins
  3. Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.

    • Pawel Buczkowicz
    • , Patricia Rakopoulos
    • , Mark Barszczyk
    • , Yevgen Chornenkyy
    •  & Cynthia Hawkins
  4. Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, North Carolina, USA.

    • Christine Hoeman
    • , Francisco Cordero
    •  & Oren Becher
  5. Génome Québec Innovation Centre, McGill University, Montreal, Quebec, Canada.

    • Louis Letourneau
    • , Mathieu Bourgey
    • , Guillaume Bourque
    •  & Alexandre Montpetit
  6. Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.

    • Misko Dzamba
    •  & Michael Brudno
  7. Laboratory of Chromatin Biology and Epigenetics, Rockefeller University, New York, New York, USA.

    • Peter Lewis
    •  & C David Allis
  8. Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Eric Bouffet
    • , Ute Bartels
    • , Uri Tabori
    •  & Annie Huang
  9. Division of Cancer Therapeutics, Institute of Cancer Research, London, UK.

    • Kathryn R Taylor
    • , Alan Mackay
    •  & Chris Jones
  10. Department of Pediatric Hematology-Oncology, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota, USA.

    • Anne E Bendel
  11. Center for Genetic Medicine, Children's National Medical Center, Washington, DC, USA.

    • Javad Nazarian
  12. Department of Pediatrics-Hematology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA.

    • Jason R Fangusaro
  13. Division of Pediatric Hematology/Oncology and Neuropathology, New York University Cancer Institute, New York University Langone Medical Center, New York, New York, USA.

    • Matthias A Karajannis
    •  & David Zagzag
  14. Department of Pediatrics, Children's Hospital Colorado, Denver, Colorado, USA.

    • Nicholas K Foreman
    •  & Andrew Donson
  15. Department of Pathology, Arnold Palmer Hospital for Children, Orlando, Florida, USA.

    • Julia V Hegert
    •  & Amy Smith
  16. Clark H. Smith Brain Tumour Centre, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.

    • Jennifer Chan
    •  & Lucy Lafay-Cousin
  17. Department of Pediatric Neurology and Neuro-Oncology, BC Children's Hospital, Vancouver, British Columbia, Canada.

    • Sandra Dunn
    • , Juliette Hukin
    •  & Chris Dunham
  18. Division of Hematology/Oncology, McMaster Children's Hospital, Hamilton, Ontario, Canada.

    • Katrin Scheinemann
  19. Department of Pathology and Laboratory Medicine, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.

    • Jean Michaud
  20. Department of Hematology/Oncology, Children's Hospital London Health Sciences Centre, London, Ontario, Canada.

    • Shayna Zelcer
    •  & David Ramsay
  21. Monash Institute of Medical Research, Monash Medical Centre, Clayton, Victoria, Australia.

    • Jason Cain
  22. Department of Neurological Surgery, Weill Cornell Medical College and Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Cameron Brennan
    •  & Mark M Souweidane
  23. The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.

    • Michael Brudno

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Contributions

E.B., U.B., P.B., O.B. and C. Hawkins designed the study. P.B., C. Hoeman, F.C., P.R., S.P., A. Morrison, J.Z., S.A., S.R., M. Barszczyk, Y.C., P.C.-B., K.C.H. and J. Mangerel performed experiments. P.B., C. Hoeman, F.C., P.R., L.L., M.D., M. Bourgey, G.B. and A. Montpetit collected and analyzed data. O.B., C. Hawkins, C.J., K.R.T., A. Mackay, A.E.B., J.N., J.R.F., M.A.K., D.Z., N.K.F., A.D., J.V.H., A.S., J. Chan, L.L.-C., S.D., J.H., C.D., K.S., J. Michaud, S.Z., D.R., J. Cain, M.M.S., E.B., U.T. and U.B. provided reagents, tissue and mice. P.B., P.R., S.P., M.D., O.B. and C. Hawkins wrote the manuscript. P.L., C.B., C.D.A., M. Brudno, A.H. and U.T. gave technical support and conceptual advice. All authors approved the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Oren Becher or Cynthia Hawkins.

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DOI

https://doi.org/10.1038/ng.2936

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