TY  - JOUR
AU  - Fontebasso, Adam M
AU  - Papillon-Cavanagh, Simon
AU  - Schwartzentruber, Jeremy
AU  - Nikbakht, Hamid
AU  - Gerges, Noha
AU  - Fiset, Pierre-Olivier
AU  - Bechet, Denise
AU  - Faury, Damien
AU  - De Jay, Nicolas
AU  - Ramkissoon, Lori A
AU  - Corcoran, Aoife
AU  - Jones, David
AU  - Sturm, Dominik
AU  - Johann, Pascal
AU  - Tomita, Tadanori
AU  - Goldman, Stewart
AU  - Nagib, Mahmoud
AU  - Bendel, Anne
AU  - Goumnerova, Liliana
AU  - Bowers, Daniel C
AU  - Leonard, Jeffrey R
AU  - Rubin, Joshua B
AU  - Alden, Tord
AU  - Browd, Samuel
AU  - Geyer, J Russell
AU  - Leary, Sarah
AU  - Jallo, George
AU  - Cohen, Kenneth
AU  - Gupta, Nalin
AU  - Prados, Michael D
AU  - Carret, Anne-Sophie
AU  - Ellezam, Benjamin
AU  - Crevier, Louis
AU  - Klekner, Almos
AU  - Bognar, Laszlo
AU  - Hauser, Peter
AU  - Garami, Miklos
AU  - Myseros, John
AU  - Dong, Zhifeng
AU  - Siegel, Peter M
AU  - Malkin, Hayley
AU  - Ligon, Azra H
AU  - Albrecht, Steffen
AU  - Pfister, Stefan
AU  - Ligon, Keith L
AU  - Majewski, Jacek
AU  - Jabado, Nada
AU  - Kieran, Mark W
TI  - Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma.
JO  - Nature genetics
VL  - 46
IS  - 5
SN  - 1546-1718
CY  - New York, NY
PB  - Nature America
M1  - DKFZ-2017-00615
SP  - 462 - 466
PY  - 2014
AB  - 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.
KW  - Bone Morphogenetic Proteins (NLM Chemicals)
KW  - Smad Proteins (NLM Chemicals)
KW  - ACVR1 protein, human (NLM Chemicals)
KW  - Activin Receptors, Type I (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:24705250
C2  - pmc:PMC4282994
DO  - DOI:10.1038/ng.2950
UR  - https://inrepo02.dkfz.de/record/120027
ER  -