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

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.

DOI: 10.1038/ng.2950

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@article{Fontebasso2014RecurrentSM, title={Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma.}, author={Adam M Fontebasso and Simon Papillon-Cavanagh and Jeremy Schwartzentruber and Hamid Nikbakht and Noha Gerges and Pierre-Olivier Fiset and Denise Bechet and Damien Faury and Nicolas De Jay and Lori A Ramkissoon and Aoife Corcoran and David T W Jones and Dominik Sturm and Pascal Johann and Tadanori Tomita and Stewart Goldman and Mahmoud Nagib and Anne Bendel and Liliana Goumnerova and Daniel C Bowers and Jeffrey R Leonard and Joshua B Rubin and Tord Alden and Samuel Browd and J Russell Geyer and Sarah Leary and George Jallo and Kenneth Cohen and Nalin Gupta and Michael D Prados and Anne-Sophie Carret and Benjamin Ellezam and Louis Crevier and Almos Klekner and Laszlo Bognar and Peter Hauser and Miklos Garami and John Myseros and Zhifeng Dong and Peter M Siegel and Hayley Malkin and Azra H Ligon and Steffen Albrecht and Stefan M Pfister and Keith L Ligon and Jacek Majewski and Nada Jabado and Mark W Kieran}, journal={Nature genetics}, year={2014}, volume={46 5}, pages={462-6} }