Journal
NATURE GENETICS
Volume 46, Issue 5, Pages 457-461Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2925
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Funding
- Cancer Research UK Genomics Initiative [A14078]
- Stavros Niarchos Foundation
- Abbie's Army
- Lyla Nsouli Foundation
- Royal Marsden Hospital Children's Department Fund
- Fondo Alicia Pueyo
- National Institutes of Neurological Disease and Stroke (NINDS) [K08NS070926]
- Alex's Lemonade Stand Foundation
- McKenna Claire Foundation
- charity l'Etoile de Martin
- Agence National de la Recherche
- Enfants et Sante
- Fundacion Cientifica de la Asociacion Espanola Contra el Cancer
- Children's Health Foundation Queensland
- Brainchild Foundation
- Canada Foundation for Innovation
- GlaxoSmithKline, Janssen, Lilly Canada
- Novartis Research Foundation
- Ontario Ministry of Economic Development and Innovation
- National Health Service (NHS)
- Cure Starts Now
- Dylan Jewett
- Elizabeth Stein
- Connor Johnson
- Zoey Ganesh Memorial Funds
- Structural Genomics Consortium [1097737]
- Canadian Institutes for Health Research, Genome Canada
- Pfizer
- Takeda
- Wellcome Trust [092809/Z/10/Z]
- Cancer Research UK [13982] Funding Source: researchfish
- Rosetrees Trust [M200-F1] Funding Source: researchfish
- The Brain Tumour Charity [16/193] Funding Source: researchfish
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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 tumorsl. We report the identification of recurrent activating mutations in the ACVR I 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.Gly328G1u, 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-beta signaling pathway. These mutations represent new targets for therapeutic intervention in this otherwise incurable disease.
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