title: Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma.
abstract: OBJECTIVE
  Long-term survival for children with diffuse intrinsic pontine glioma (DIPG) is less than 10%, and new therapeutic targets are urgently required. We evaluated a large cohort of DIPGs to identify recurrent genomic abnormalities and gene expression signatures underlying DIPG.
  
  
  METHODS
  Single-nucleotide polymorphism arrays were used to compare the frequencies of genomic copy number abnormalities in 43 DIPGs and eight low-grade brainstem gliomas with data from adult and pediatric (non-DIPG) glioblastomas, and expression profiles were evaluated using gene expression arrays for 27 DIPGs, six low-grade brainstem gliomas, and 66 nonbrainstem low-grade gliomas.
  
  
  RESULTS
  Frequencies of specific large-scale and focal imbalances varied significantly between DIPGs and nonbrainstem pediatric glioblastomas. Focal amplifications of genes within the receptor tyrosine kinase-Ras-phosphoinositide 3-kinase signaling pathway were found in 47% of DIPGs, the most common of which involved PDGFRA and MET. Thirty percent of DIPGs contained focal amplifications of cell-cycle regulatory genes controlling retinoblastoma protein (RB) phosphorylation, and 21% had concurrent amplification of genes from both pathways. Some tumors showed heterogeneity in amplification patterns. DIPGs showed distinct gene expression signatures related to developmental processes compared with nonbrainstem pediatric high-grade gliomas, whereas expression signatures of low-grade brainstem and nonbrainstem gliomas were similar.
  
  
  CONCLUSIONS
  DIPGs comprise a molecularly related but distinct subgroup of pediatric gliomas. Genomic studies suggest that targeted inhibition of receptor tyrosine kinases and RB regulatory proteins may be useful therapies for DIPG.
authors.affiliation: St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Barbara S
authors.initials: BS
authors.lastname: Paugh
authors.forename: Alberto
authors.initials: A
authors.lastname: Broniscer
authors.forename: Chunxu
authors.initials: C
authors.lastname: Qu
authors.forename: Claudia P
authors.initials: CP
authors.lastname: Miller
authors.forename: Junyuan
authors.initials: J
authors.lastname: Zhang
authors.forename: Ruth G
authors.initials: RG
authors.lastname: Tatevossian
authors.forename: James M
authors.initials: JM
authors.lastname: Olson
authors.forename: J Russell
authors.initials: JR
authors.lastname: Geyer
authors.forename: Susan N
authors.initials: SN
authors.lastname: Chi
authors.forename: Nasjla Saba
authors.initials: NS
authors.lastname: da Silva
authors.forename: Arzu
authors.initials: A
authors.lastname: Onar-Thomas
authors.forename: Justin N
authors.initials: JN
authors.lastname: Baker
authors.forename: Amar
authors.initials: A
authors.lastname: Gajjar
authors.forename: David W
authors.initials: DW
authors.lastname: Ellison
authors.forename: Suzanne J
authors.initials: SJ
authors.lastname: Baker
mesh_terms: D000328:Adult; D020295:Brain Stem Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D005784:Gene Amplification; D018628:Gene Dosage; D020869:Gene Expression Profiling; D018816:Genes, cdc; D055106:Genome-Wide Association Study; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D020641:Polymorphism, Single Nucleotide; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D016160:Retinoblastoma Protein; D020794:Receptor Protein-Tyrosine Kinases