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Series GSE46190 Query DataSets for GSE46190
Status Public on Nov 06, 2013
Title Novel Oncogenic PDGFRA Mutations in Pediatric High-Grade Gliomas
Organism Mus musculus
Experiment type Expression profiling by array
Summary 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.
 
Overall design 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.
 
Contributor(s) Paugh BS, Zhu X, Baker SJ
Citation(s) 23970477
Submission date Apr 18, 2013
Last update date Aug 06, 2018
Contact name Chunxu Qu
E-mail(s) chunxu.qu@stjude.org
Phone 9015952433
Organization name St Jude Children's Research Institute
Department Pathology
Lab Mullighan
Street address 262 Danny Thomas Pl
City Memphis
State/province TN
ZIP/Postal code 38105
Country USA
 
Platforms (1)
GPL11180 [HT_MG-430_PM] Affymetrix HT MG-430 PM Array Plate
Samples (45)
GSM1125911 PDGFRA-driven Glioblastoma mouse model with p53 null background, pdg023
GSM1125912 EGFRvIII-driven Glioblastoma mouse model with p53 null background, pdg042
GSM1125913 PDGFRA-driven Glioblastoma mouse model with p53 null background, pdg057
Relations
BioProject PRJNA198017

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE46190_RAW.tar 96.7 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table
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