Journal
NATURE GENETICS
Volume 46, Issue 5, Pages 444-450Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2938
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Funding
- St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project
- American Lebanese and Syrian Associated Charities (ALSAC) of St. Jude Children's Research Hospital
- US National Institutes of Health [P01 CA096832, R01 CA135554]
- Cure Starts Now Foundation
- Smile for Sophie Forever Foundation
- Tyler's Treehouse and Musicians Against Childhood Cancer
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Pediatric high-grade glioma (HGG) is a devastating disease with a less than 20% survival rate 2 years after diagnosis(1). 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(2-5). 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.
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