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.

• Authors: Adam M Fontebasso, Simon Papillon-Cavanagh, Jeremy Schwartzentruber, Hamid Nikbakht, Noha Gerges, Pierre-Olivier Fiset, Denise Bechet, Damien Faury, Nicolas De Jay, Lori A Ramkissoon, Aoife Corcoran, David T W Jones, Dominik Sturm, Pascal Johann, Tadanori Tomita, Stewart Goldman, Mahmoud Nagib, Anne Bendel, Liliana Goumnerova, Daniel C Bowers, Jeffrey R Leonard, Joshua B Rubin, Tord Alden, Samuel Browd, J Russell Geyer, Sarah Leary, George Jallo, Kenneth Cohen, Nalin Gupta, Michael D Prados, Anne-Sophie Carret, Benjamin Ellezam, Louis Crevier, Almos Klekner, Laszlo Bognar, Peter Hauser, Miklos Garami, John Myseros, Zhifeng Dong, Peter M Siegel, Hayley Malkin, Azra H Ligon, Steffen Albrecht, Stefan M Pfister, Keith L Ligon, Jacek Majewski, Nada Jabado, Mark W Kieran
• Journal: Nature genetics (Nat Genet) Vol. 46 Issue 5 Pg. 462-6 (May 2014) ISSN: 1546-1718 [Electronic] United States
• PMID: 24705250 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Bone Morphogenetic Proteins
• Smad Proteins
• ACVR1 protein, human
• Activin Receptors, Type I

Topics

• Activin Receptors, Type I (genetics)
• Animals
• Astrocytoma (genetics)
• Base Sequence
• Bone Morphogenetic Proteins (metabolism)
• Brain Neoplasms (genetics)
• Child
• DNA Copy Number Variations (genetics)
• DNA Methylation (genetics)
• Gene Expression Regulation, Neoplastic (genetics)
• Genome, Human (genetics)
• Humans
• Immunohistochemistry
• In Situ Hybridization, Fluorescence
• Molecular Sequence Data
• Mutation (genetics)
• Sequence Analysis, DNA
• Smad Proteins (metabolism)