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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.

SUBMITTER: Fontebasso AM

PROVIDER: S-EPMC4282994 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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

Fontebasso Adam M AM Papillon-Cavanagh Simon S Schwartzentruber Jeremy J Nikbakht Hamid H Gerges Noha N Fiset Pierre-Olivier PO Bechet Denise D Faury Damien D De Jay Nicolas N Ramkissoon Lori A LA Corcoran Aoife A Jones David T W DT Sturm Dominik D Johann Pascal P Tomita Tadanori T Goldman Stewart S Nagib Mahmoud M Bendel Anne A Goumnerova Liliana L Bowers Daniel C DC Leonard Jeffrey R JR Rubin Joshua B JB Alden Tord T Browd Samuel S Geyer J Russell JR Leary Sarah S Jallo George G Cohen Kenneth K Gupta Nalin N Prados Michael D MD Carret Anne-Sophie AS Ellezam Benjamin B Crevier Louis L Klekner Almos A Bognar Laszlo L Hauser Peter P Garami Miklos M Myseros John J Dong Zhifeng Z Siegel Peter M PM Malkin Hayley H Ligon Azra H AH Albrecht Steffen S Pfister Stefan M SM Ligon Keith L KL Majewski Jacek J Jabado Nada N Kieran Mark W MW

Nature genetics 20140406 5

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 associate ...[more]

PMID: 24705250

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Project description:The outcome for children with high-grade gliomas (HGG) remains dismal, with a two-year survival rate of only 10-30%. Approximately half of pediatric HGGs are diffuse intrinsic pontine glioma (DIPG), a brainstem tumor that arises almost exclusively in children. Genome-wide analyses of copy number imbalances previously showed that platelet derived growth factor receptor alpha (PDGFRA) is the most frequent target of focal amplification in pediatric HGGs. To determine whether the PDGFRA is also targeted by more subtle mutations not detected by copy number analysis, we sequenced all PDGFRA coding exons from a cohort of pediatric HGGs. Somatic activating mutations were identified in 14.4% (13/90) of non-brainstem pediatric HGGs and 4.7% (2/43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described. 40% of tumors with mutation showed concurrent amplification, while 60% carried heterozygous mutations. Six different mutations impacting different domains all resulted in ligand-independent receptor activation that was blocked by small molecule inhibitors of PDGFR. Expression of mutants in p53-null primary mouse astrocytes conferred a proliferative advantage in vitro, and generated HGGs in vivo with complete penetrance when implanted into brain. The gene expression signatures reflected the spectrum of human diffuse HGGs. PDGFRA intragenic deletion of exons 8 and 9 were previously shown in adult HGG, but were not detected in 83 non-brainstem pediatric HGG and 57 DIPGs. Thus, a distinct spectrum of mutations confers constitutive receptor activation and oncogenic activity to PDGFR in childhood HGG. To better understand the consequence of PDGFRα mutation in pediatric gliomagenesis, retroviral constructs expressing wild-type PDGFRα or six selected PDGFRα mutants that affect different regions of the receptor were generated for functional studies. p53-null primary mouse astrocyte (PMA) cultures were chosen as a relevant cellular background to assess PDGFRα function.

Dataset Information

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

Publications

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

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