Unknown,Transcriptomics,Genomics,Proteomics

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The landscape of somatic alterations in epigenetic genes across 21 pediatric cancers

ABSTRACT: As a part of the St Jude Children’s Research Hospital-Washington University Pediatric Cancer Genome Project (PCGP), we adapted deep sequencing technologies and have sequenced 1025 tumor samples from 21 diseases covering brain, solid tumors and leukemias. We analyzed the genomic DNA sequences, copy number variations and structural rearrangements of 633 genes whose proteins are involved in epigenetic machineries, including those that covalently modify DNA and histones, and structurally reorder chromatin. To examine gene expression level of mutated histone genes, we analyzed gene expression in a group of 40 non-ETP T-lineage ALL samples using Affymetrix GeneChip HT HG-U133+ PM arrays (including 37 samples deposited in GSE28703 and 3 additional arrays not studied previously). The results provide us the knowledge of potential therapeutic targets for pediatric cancer treatment and improvement of personalized therapy. Gene expression profiling was performed on 40 non ETP T-lineage acute lymphoblastic leukemia samples. No control or reference samples were included.

ORGANISM(S): Homo sapiens

SUBMITTER: Shann-Ching Chen

PROVIDER: E-GEOD-43209 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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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The landscape of somatic alterations in epigenetic genes across 21 pediatric cancers

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