Abstract

Diffuse intrinsic pontine gliomas (DIPGs) are highly infiltrative malignant glial neoplasms of the ventral pons that, due to their location within the brain, are unsuitable for surgical resection and consequently have a universally dismal clinical outcome. The median survival time is 9–12 months, with neither chemotherapeutic nor targeted agents showing substantial survival benefit in clinical trials in children with these tumors1. We report the identification of recurrent activating mutations in the ACVR1 gene, which encodes a type I activin receptor serine/threonine kinase, in 21% of DIPG samples. Strikingly, these somatic mutations (encoding p.Arg206His, p.Arg258Gly, p.Gly328Glu, p.Gly328Val, p.Gly328Trp and p.Gly356Asp substitutions) have not been reported previously in cancer but are identical to mutations found in the germ line of individuals with the congenital childhood developmental disorder fibrodysplasia ossificans progressiva (FOP)2 and have been shown to constitutively activate the BMP–TGF-β signaling pathway. These mutations represent new targets for therapeutic intervention in this otherwise incurable disease.

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Acknowledgements

This study was funded by the Cancer Research UK Genomics Initiative (A14078) and makes use of data generated by the St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project. We are grateful to the DIPG Preclinical Consortium funded by The Cure Starts Now and the Lyla Nsouli Foundation for RNA-seq data. This work is supported by the Stavros Niarchos Foundation, Abbie's Army, the Lyla Nsouli Foundation, the Royal Marsden Hospital Children's Department Fund and Fondo Alicia Pueyo. M.M. gratefully acknowledges funding by the National Institutes of Neurological Disease and Stroke (NINDS; grant K08NS070926), Alex's Lemonade Stand Foundation, the McKenna Claire Foundation and the Dylan Jewett, Elizabeth Stein, Connor Johnson and Zoey Ganesh Memorial Funds. C.P. acknowledges funding from the Agence National de la Recherche. N.T., C.P. and J.G. acknowledge funding from the charity l'Etoile de Martin, and N.E.-W. acknowledges support from Enfants et Santé. A.M.C. acknowledges funding from the Fundación Científica de la Asociación Española Contra el Cáncer. W.J.I. acknowledges funding from the Children's Health Foundation Queensland and the Brainchild Foundation. The Structural Genomics Consortium is a registered charity (1097737) that receives funds from AbbVie, Boehringer Ingelheim, the Canada Foundation for Innovation, the Canadian Institutes for Health Research, Genome Canada, GlaxoSmithKline, Janssen, Lilly Canada, the Novartis Research Foundation, the Ontario Ministry of Economic Development and Innovation, Pfizer, Takeda and the Wellcome Trust (092809/Z/10/Z). K.R.T., A.M., M.V., D. Carvalho, D.H. and C.J. acknowledge National Health Service (NHS) funding to the National Institute of Health Research Biomedical Research Centres.

Author information

Author notes

    • Kathryn R Taylor
    •  & Alan Mackay

    These authors contributed equally to this work.

Affiliations

  1. Institute of Cancer Research, London, UK.

    • Kathryn R Taylor
    • , Alan Mackay
    • , Maria Vinci
    • , Diana Carvalho
    •  & Chris Jones
  2. CNRS UMR 8203, Gustave Roussy, University Paris Sud, Villejuif, France.

    • Nathalène Truffaux
    • , Cathy Philippe
    • , David Castel
    •  & Jacques Grill
  3. BC Cancer Agency, Vancouver, British Columbia, Canada.

    • Yaron S Butterfield
    •  & Stephen Yip
  4. Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, California, USA.

    • Olena Morozova
  5. Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA.

    • Catherine S Grasso
  6. Pediatric Hematology and Oncology, Hospital Sant Joan de Déu, Barcelona, Spain.

    • Angel M Carcaboso
    • , Carmen de Torres
    • , Ofelia Cruz
    •  & Jaume Mora
  7. Centre Hospitalier Regional et Universitaire Hautepierre, Strasbourg, France.

    • Natacha Entz-Werle
  8. Queensland Children's Tumour Bank, Queensland Children's Medical Research Institute, The University of Queensland, Brisbane, Queensland, Australia.

    • Wendy J Ingram
  9. Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California, USA.

    • Michelle Monje
  10. Neuro-oncology and Experimental Therapeutics, Great Ormond Street Hospital, London, UK.

    • Darren Hargrave
  11. Structural Genomics Consortium, University of Oxford, Oxford, UK.

    • Alex N Bullock
  12. Pediatric Neurosurgery, Necker Sick Children's Hospital, Paris, France.

    • Stéphanie Puget

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Contributions

C.J., J.G., D.H. and S.Y. designed the study. C.J. wrote the manuscript. K.R.T., A.M. and C.J. designed and reviewed experiments, and designed and reviewed statistical and bioinformatic analyses. K.R.T. performed experiments. A.M. performed bioinformatic analyses. N.T., D. Castel, M.V. and D. Carvalho performed sample preparation and experiments. Y.S.B., O.M., C.P., C.S.G. and S.Y. performed and reviewed bioinformatic analyses. A.M.C., C.d.T., O.C., J.M., N.E.-W., W.J.I., M.M., A.N.B., S.P. and J.G. provided and prepared samples and experimental materials. All authors reviewed the manuscript during its preparation.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Chris Jones or Jacques Grill.

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    Supplementary Table 1

    Full list of somatic coding variants in 26 cases of DIPG.

About this article

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DOI

https://doi.org/10.1038/ng.2925

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