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Nat Genet. 2014 May;46(5):457-461. doi: 10.1038/ng.2925. Epub 2014 Apr 6.

Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma.

Author information

1
Institute of Cancer Research, London, UK.
2
Institut Gustav Roussy, Villejuif, France.
3
BC Cancer Agency, Vancouver, Canada.
4
Howard Hughes Medical Institute, Los Angeles, CA, USA.
5
University of California, Los Angeles, CA, USA.
6
Oregon Health and Science University, Portland, OR, USA.
7
Hospital Sant Joan de Deu, Barcelona, Spain.
8
Centre Hospitalier Régional et Universitaire Hautepierre, Strasbourg, France.
9
Queensland Children's Tumour Bank, Queensland Children's Medical Research Institute, The University of Queensland, Brisbane, Queensland, Australia.
10
Stanford University School of Medicine, Stanford, CA, USA.
11
Great Ormond Street Hospital, London, UK.
12
Structural Genomics Consortium, University of Oxford, UK.
13
Necker Childrens Hospital, Paris, France.
#
Contributed equally

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 tumors. 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) 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.

PMID:
24705252
PMCID:
PMC4018681
DOI:
10.1038/ng.2925
[Indexed for MEDLINE]
Free PMC Article

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