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Next Generation Sequencing Analysis of Human Glioblastoma Transcriptomes And Quantitative Analysis of PDGFRA Positive/Negative Human Glioma Cells Transcriptomes

ABSTRACT: We report the high-throughput profiling of thirteen human glioblastoma and four pairs of panned(pdgfra+) and supernatant(pdgfra-) human glioma cells. The subtypes and the different expression genes(DEGs) was identified integrated genomic analysis:single sample GSEA and DESeq.We obtained the enrichment gene pathway by using Gene Ontology Enrichment analysis-Functional classification viewed in pie chart.We find that the features of Proneural were enriched generaly when comparing the four pairs of the panned(pdgfra+) and supernatant(pdgfra-) human glioma cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE108862 | GEO | 2020/09/10

REPOSITORIES: GEO

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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.

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Next Generation Sequencing Analysis of Human Glioblastoma Transcriptomes And Quantitative Analysis of PDGFRA Positive/Negative Human Glioma Cells Transcriptomes

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