Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas

The outcome for children with high-grade gliomas (HGG) remains dismal, with a 2-year survival rate of only 10% to 30%. Diffuse intrinsic pontine glioma (DIPG) comprise a subset of HGG that arise in the brainstem almost exclusively in children. Genome-wide analyses of copy number imbalances previousl...

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Veröffentlicht in:Cancer research (Chicago, Ill.) Jg. 73; H. 20; S. 6219
Hauptverfasser: Paugh, Barbara S, Zhu, Xiaoyan, Qu, Chunxu, Endersby, Raelene, Diaz, Alexander K, Zhang, Junyuan, Bax, Dorine A, Carvalho, Diana, Reis, Rui M, Onar-Thomas, Arzu, Broniscer, Alberto, Wetmore, Cynthia, Zhang, Jinghui, Jones, Chris, Ellison, David W, Baker, Suzanne J
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States 15.10.2013
Schlagworte:
Adolescent
Animals
Brain Neoplasms - genetics
Brain Neoplasms - pathology
Child
Child, Preschool
Gene Expression Profiling
Genome-Wide Association Study
Glioma - genetics
Glioma - pathology
Humans
Mice
Mutation
Receptor, Platelet-Derived Growth Factor alpha - genetics
Receptor, Platelet-Derived Growth Factor alpha - metabolism
ISSN:1538-7445, 1538-7445
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Zusammenfassung:The outcome for children with high-grade gliomas (HGG) remains dismal, with a 2-year survival rate of only 10% to 30%. Diffuse intrinsic pontine glioma (DIPG) comprise a subset of HGG that arise in the brainstem almost exclusively in children. Genome-wide analyses of copy number imbalances previously showed that platelet-derived growth factor receptor α (PDGFRA) is the most frequent target of focal amplification in pediatric HGGs, including DIPGs. To determine whether PDGFRA is also targeted by more subtle mutations missed 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 of 90) of nonbrainstem pediatric HGGs and 4.7% (2 of 43) of DIPGs, including missense mutations and in-frame deletions and insertions not previously described. Forty percent of tumors with mutation showed concurrent amplification, whereas 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 of these murine HGGs 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 nonbrainstem pediatric HGG and 57 DIPGs. Thus, a distinct spectrum of mutations confers constitutive receptor activation and oncogenic activity to PDGFRα in childhood HGG.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:1538-7445
1538-7445
DOI:10.1158/0008-5472.CAN-13-1491