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Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma

Fontebasso, Adam M. and Papillon-Cavanagh, Simon and Schwartzentruber, Jeremy and Nikbakht, Hamid and Gerges, Noha and Klekner, Almos and Bognar, Laszlo and Hauser, Peter and Garami, Miklos (2014) Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nature Genetics, 46 (5). pp. 462-466. ISSN 1061-4036

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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.

Item Type: Article
Additional Information: Teljes szerzőség: Fontebasso, Adam M. és Papillon-Cavanagh, Simon és Schwartzentruber, Jeremy és Nikbakht, Hamid és Gerges, Noha és Fiset, Pierre-Olivier és Bechet, Denise és Faury, Damien és De Jay, Nicolas és Ramkissoon, Lori A. és Corcoran, Aoife és Jones, David T. W. és Sturm, Dominik és Johann, Pascal és Tomita, Tadanori és Goldman, Stewart és Nagib, Mahmoud és Bendel, Anne és Goumnerova, Liliana és Bowers, Daniel C. és Leonard, Jeffrey R. és Rubin, Joshua B. és Alden, Tord és Browd, Samuel és Geyer, Russell J. és Leary, Sarah és Jallo, George és Cohen, Kenneth és Gupta, Nalin és Prados, Michael D. és Carret, Anne-Sophie és Ellezam, Benjamin és Crevier, Louis és Klekner, Almos és Bognar, Laszlo és Hauser, Peter és Garami, Miklos és Myseros, John és Dong, Zhifeng és Siegel, Peter M. és Malkin, Hayley és Ligon, Azra H. és Albrecht, Steffen és Pfister, Stefan M. és Ligon, Keith L. és Majewski, Jacek és Jabado, Nada és Kieran, Mark W.
Subjects: R Medicine / orvostudomány > RC Internal medicine / belgyógyászat > RC0254 Neoplasms. Tumors. Oncology (including Cancer) / daganatok, tumorok, onkológia
Depositing User: Dr. Álmos Klekner
Date Deposited: 17 Nov 2014 07:46
Last Modified: 01 May 2016 23:15
URI: http://real.mtak.hu/id/eprint/15792

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