Abstract

Pediatric midline high-grade astrocytomas (mHGAs) are incurable with few treatment targets identified. Most tumors harbor mutations encoding p.Lys27Met in histone H3 variants. In 40 treatment-naive mHGAs, 39 analyzed by whole-exome sequencing, we find additional somatic mutations specific to tumor location. Gain-of-function mutations in ACVR1 occur in tumors of the pons in conjunction with histone H3.1 p.Lys27Met substitution, whereas FGFR1 mutations or fusions occur in thalamic tumors associated with histone H3.3 p.Lys27Met substitution. Hyperactivation of the bone morphogenetic protein (BMP)-ACVR1 developmental pathway in mHGAs harboring ACVR1 mutations led to increased levels of phosphorylated SMAD1, SMAD5 and SMAD8 and upregulation of BMP downstream early-response genes in tumor cells. Global DNA methylation profiles were significantly associated with the p.Lys27Met alteration, regardless of the mutant histone H3 variant and irrespective of tumor location, supporting the role of this substitution in driving the epigenetic phenotype. This work considerably expands the number of potential treatment targets and further justifies pretreatment biopsy in pediatric mHGA as a means to orient therapeutic efforts in this disease.

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Acknowledgements

The authors would like to express their sincere gratitude toward all staff at the McGill University and Génome Québec Innovation Centre for excellent technical expertise, library preparation and sequencing. The authors are very grateful to J.-J. Lebrun (McGill University) for primer sequences and materials for SMAD signaling studies. This work was performed within the context of the I-CHANGE (International Childhood Astrocytoma Integrated Genomics and Epigenomics) Consortium and was supported by funding from Genome Canada, Génome Québec, the Institute for Cancer Research of the Canadian Institutes for Health Research (CIHR), McGill University and the Montreal Children's Hospital Foundation. This work was also supported by Hungarian Scientific Research Fund (OTKA) contract T-04639, National Research and Development Fund (NKFP) contract 1A/002/2004 (P.H. and M.G.) and TÁMOP-4.2.2A-11/1/KONV-2012-0025 (A.K. and L.B.). N.J. is a member of the Penny Cole laboratory and the recipient of a Chercheur Clinicien Senior Award. J. Majewski holds a Canada Research Chair (tier 2). L.G., K.L.L. and M.W.K. are supported by NCI P01CA142536. We acknowledge the support of the Zach Carson DIPG Fund at the Dana-Farber Cancer Institute (DFCI), the Ellie Kavalieros Fund (DFCI), the Mikey Czech Foundation, the Prayer From Maria Foundation, the Hope for Caroline Fund (DFCI), the Ryan Harvey DIPG Fund (DFCI), the Stop&Shop Pediatric Brain Tumor Program (DFCI) and the Pediatric Brain Tumor Clinical and Research Fund (DFCI). A.M.F. is supported by a studentship from CIHR, as well as by an award from the CIHR Systems Biology Training Program at McGill University. D.B. is supported by a studentship from the T.D. Trust/Montreal Children's Hospital Foundation, and N. Gerges is supported by a studentship from the Cedars Cancer Institute. N.D.J. is supported by an award from the McGill Integrated Cancer Research Training Program.

Author information

Author notes

    • Adam M Fontebasso
    • , Simon Papillon-Cavanagh
    •  & Jeremy Schwartzentruber

    These authors contributed equally to this work.

    • Keith L Ligon
    • , Jacek Majewski
    • , Nada Jabado
    •  & Mark W Kieran

    These authors jointly directed this work.

Affiliations

  1. Division of Experimental Medicine, Montreal Children′s Hospital, McGill University and McGill University Health Centre, Montreal, Quebec, Canada.

    • Adam M Fontebasso
    •  & Nada Jabado
  2. Department of Human Genetics, McGill University, Montreal, Quebec, Canada.

    • Simon Papillon-Cavanagh
    • , Hamid Nikbakht
    • , Noha Gerges
    • , Denise Bechet
    • , Damien Faury
    • , Nicolas De Jay
    • , Jacek Majewski
    •  & Nada Jabado
  3. Wellcome Trust Sanger Institute, Hinxton, UK.

    • Jeremy Schwartzentruber
  4. Department of Pathology, Montreal Children′s Hospital, McGill University Health Centre, Montreal, Quebec, Canada.

    • Pierre-Olivier Fiset
    •  & Steffen Albrecht
  5. Department of Pediatrics, McGill University, Montreal, Quebec, Canada.

    • Damien Faury
    •  & Nada Jabado
  6. Department of Medical Oncology, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Lori A Ramkissoon
    • , Aoife Corcoran
    • , Azra H Ligon
    •  & Keith L Ligon
  7. Division of Pediatric Neuro-oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • David T W Jones
    • , Dominik Sturm
    • , Pascal Johann
    •  & Stefan M Pfister
  8. Department of Neurological Surgery, Ann & Robert H. Lurie Children′s Hospital of Chicago, Northwestern University, Chicago, Illinois, USA.

    • Tadanori Tomita
    •  & Tord Alden
  9. Department of Pediatrics Hematology-Oncology, Ann & Robert H. Lurie Children′s Hospital of Chicago, Northwestern University, Chicago, Illinois, USA.

    • Stewart Goldman
  10. Clinical Pediatric Neurosurgical Oncology, Department of Surgery, Boston Children′s Hospital, Boston, Massachusetts, USA.

    • Mahmoud Nagib
  11. Department of Pediatric Hematology-Oncology, Children′s Hospitals and Clinics of Minnesota, Minneapolis, Minnesota, USA.

    • Anne Bendel
  12. Department of Neurosurgery, Boston Children′s Hospital, Boston, Massachusetts, USA.

    • Liliana Goumnerova
  13. Harvard Medical School, Boston, Massachusetts, USA.

    • Liliana Goumnerova
    • , Azra H Ligon
    • , Keith L Ligon
    •  & Mark W Kieran
  14. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

    • Daniel C Bowers
  15. Department of Neurological Surgery, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.

    • Jeffrey R Leonard
  16. Department of Pediatrics, Hematology-Oncology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.

    • Joshua B Rubin
  17. Department of Neurosurgery, Seattle Children′s Hospital, Seattle, Washington, USA.

    • Samuel Browd
  18. Cancer and Blood Disorders Center, Seattle Children′s Hospital, Seattle, Washington, USA.

    • J Russell Geyer
    •  & Sarah Leary
  19. Department of Neurological Surgery, Johns Hopkins Hospital, Baltimore, Maryland, USA.

    • George Jallo
  20. Department of Pediatric Hematology-Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.

    • Kenneth Cohen
  21. Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.

    • Nalin Gupta
    •  & Michael D Prados
  22. Department of Hematology-Oncology, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada.

    • Anne-Sophie Carret
  23. Department of Pathology, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada.

    • Benjamin Ellezam
  24. Department of Neurosurgery, Centre Hospitalier Universitaire (CHU) Sainte-Justine, Université de Montréal, Montreal, Quebec, Canada.

    • Louis Crevier
  25. Department of Neurosurgery, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary.

    • Almos Klekner
    •  & Laszlo Bognar
  26. 2nd Department of Paediatrics, Semmelweis University, Budapest, Hungary.

    • Peter Hauser
    •  & Miklos Garami
  27. Department of Neurosurgery, Children′s National Medical Center, Washington, DC, USA.

    • John Myseros
  28. Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, Canada.

    • Zhifeng Dong
    •  & Peter M Siegel
  29. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Hayley Malkin
    •  & Mark W Kieran
  30. Department of Pathology, Brigham and Women′s Hospital, Boston, Massachusetts, USA.

    • Azra H Ligon
    •  & Keith L Ligon
  31. Department of Pathology, Boston Children′s Hospital, Boston, Massachusetts, USA.

    • Keith L Ligon
  32. Division of Pediatric Hematology/Oncology, Boston Children′s Hospital, Boston, Massachusetts, USA.

    • Mark W Kieran

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Contributions

A.M.F., N. Gerges, P.-O.F., D.B., D.F., L.A.R., A.C., A.H.L., S.A. and Z.D. performed experiments. A.M.F., S.P.-C., J.S., H.N., N.D.J., A.H.L., S.A., Z.D. and P.M.S. analyzed the data and produced figures and tables. D.T.W.J., D.S., P.J., T.T., S.G., M.N., A.B., L.G., D.C.B., J.R.L., J.B.R., T.A., S.B., J.R.G., G.J., K.C., N. Gupta, M.D.P., A.-S.C., B.E., L.C., A.K., L.B., P.H., M.G., J. Myseros, H.M., S.A. and S.M.P. provided tissue samples. K.L.L., J. Majewski, N.J. and M.W.K. provided project leadership and designed the study. All authors contributed to the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Keith L Ligon or Jacek Majewski or Nada Jabado or Mark W Kieran.

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DOI

https://doi.org/10.1038/ng.2950

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