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Nat Genet. 2014 May;46(5):444-450. doi: 10.1038/ng.2938. Epub 2014 Apr 6.

The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma.

Author information

1
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
2
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105.
3
Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN 38163.
4
Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, TN 38105.
5
Department of Pediatric Cancer Genome Project, St. Jude Children's Research Hospital, Memphis, TN 38105.
6
The Genome Institute, Washington University, 633108.
7
Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN 38105.
8
Department of Structural Biology, St. Jude Children's Research Hospital, Memphis, TN 38105.
9
Biostatistics and Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY 14263.
10
Division of Molecular Pathology, Institute for Cancer Research, London, UK SM2 5NG.
11
Division of Cancer Therapeutics, Institute for Cancer Research, London, UK SM2 5NG.
12
Department of Surgery, St. Jude Children's Research Hospital, Memphis, TN 38105.
13
Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105.
14
Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN 38105.
#
Contributed equally

Abstract

Pediatric high-grade glioma (HGG) is a devastating disease with a less than 20% survival rate 2 years after diagnosis. We analyzed 127 pediatric HGGs, including diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGGs (NBS-HGGs), by whole-genome, whole-exome and/or transcriptome sequencing. We identified recurrent somatic mutations in ACVR1 exclusively in DIPGs (32%), in addition to previously reported frequent somatic mutations in histone H3 genes, TP53 and ATRX, in both DIPGs and NBS-HGGs. Structural variants generating fusion genes were found in 47% of DIPGs and NBS-HGGs, with recurrent fusions involving the neurotrophin receptor genes NTRK1, NTRK2 and NTRK3 in 40% of NBS-HGGs in infants. Mutations targeting receptor tyrosine kinase-RAS-PI3K signaling, histone modification or chromatin remodeling, and cell cycle regulation were found in 68%, 73% and 59% of pediatric HGGs, respectively, including in DIPGs and NBS-HGGs. This comprehensive analysis provides insights into the unique and shared pathways driving pediatric HGG within and outside the brainstem.

PMID:
24705251
PMCID:
PMC4056452
DOI:
10.1038/ng.2938
[Indexed for MEDLINE]
Free PMC Article
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