Journal Article

DKFZ-2017-00615

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma.

Fontebasso, A. M. ; Papillon-Cavanagh, S. ; Schwartzentruber, J. ; Nikbakht, H. ; Gerges, N. ; Fiset, P.-O. ; Bechet, D. ; Faury, D. ; De Jay, N. ; Ramkissoon, L. A. ; Corcoran, A. ; Jones, D.DKFZ* ; Sturm, D.DKFZ* ; Johann, P.DKFZ* ; Tomita, T. ; Goldman, S. ; Nagib, M. ; Bendel, A. ; Goumnerova, L. ; Bowers, D. C. ; Leonard, J. R. ; Rubin, J. B. ; Alden, T. ; Browd, S. ; Geyer, J. R. ; Leary, S. ; Jallo, G. ; Cohen, K. ; Gupta, N. ; Prados, M. D. ; Carret, A.-S. ; Ellezam, B. ; Crevier, L. ; Klekner, A. ; Bognar, L. ; Hauser, P. ; Garami, M. ; Myseros, J. ; Dong, Z. ; Siegel, P. M. ; Malkin, H. ; Ligon, A. H. ; Albrecht, S. ; Pfister, S.DKFZ* ; Ligon, K. L. ; Majewski, J. ; Jabado, N. ; Kieran, M. W.

2014
Nature America New York, NY

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Please use a persistent id in citations: doi:10.1038/ng.2950

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.

Keyword(s): Bone Morphogenetic Proteins ; Smad Proteins ; ACVR1 protein, human ; Activin Receptors, Type I

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Contributing Institute(s):

1. Pädiatrische Neuroonkologie (B062)

Research Program(s):

1. 312 - Functional and structural genomics (POF3-312) (POF3-312)

Appears in the scientific report 2014

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Database coverage:
; BIOSIS Previews ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 30 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Thomson Reuters Master Journal List ; Web of Science Core Collection

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