Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma.
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.
Institute of Cancer Research, London, UK.
Kathryn R
KR
Taylor
Institute of Cancer Research, London, UK.
Alan
A
Mackay
Institut Gustav Roussy, Villejuif, France.
Nathalène
N
Truffaux
BC Cancer Agency, Vancouver, Canada.
Yaron
Y
Butterfield
Howard Hughes Medical Institute, Los Angeles, CA, USA.|University of California, Los Angeles, CA, USA.
Olena
O
Morozova
Institut Gustav Roussy, Villejuif, France.
Cathy
C
Philippe
Institut Gustav Roussy, Villejuif, France.
David
D
Castel
Oregon Health and Science University, Portland, OR, USA.
Catherine S
CS
Grasso
Institute of Cancer Research, London, UK.
Maria
M
Vinci
Institute of Cancer Research, London, UK.
Diana
D
Carvalho
Hospital Sant Joan de Deu, Barcelona, Spain.
Angel M
AM
Carcaboso
Hospital Sant Joan de Deu, Barcelona, Spain.
Carmen
C
de Torres
Hospital Sant Joan de Deu, Barcelona, Spain.
Ofelia
O
Cruz
Hospital Sant Joan de Deu, Barcelona, Spain.
Jaume
J
Mora
Centre Hospitalier Régional et Universitaire Hautepierre, Strasbourg, France.
Natacha
N
Entz-Werle
Queensland Children's Tumour Bank, Queensland Children's Medical Research Institute, The University of Queensland, Brisbane, Queensland, Australia.
Wendy J
WJ
Ingram
Stanford University School of Medicine, Stanford, CA, USA.
Michelle
M
Monje
Great Ormond Street Hospital, London, UK.
Darren
D
Hargrave
Structural Genomics Consortium, University of Oxford, UK.
Alex N
AN
Bullock
Necker Childrens Hospital, Paris, France.
Stéphanie
S
Puget
BC Cancer Agency, Vancouver, Canada.
Stephen
S
Yip
Institute of Cancer Research, London, UK.
Chris
C
Jones
Institut Gustav Roussy, Villejuif, France.
Jacques
J
Grill
D030201:Activin Receptors, Type I / Q000235:genetics*; D001483:Base Sequence; D020295:Brain Stem Neoplasms / Q000145:classification / Q000235:genetics*; D002648:Child; D015331:Cohort Studies; D059472:Exome / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D005910:Glioma / Q000145:classification / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D009221:Myositis Ossificans / Q000235:genetics; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics
C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I