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Semin Radiat Oncol. 2014 Oct;24(4):240-7. doi: 10.1016/j.semradonc.2014.06.003.

The genetic signatures of pediatric high-grade glioma: no longer a one-act play.

Author information

1
Developmental Neurobiology, St. Jude Children׳s Research Hospital, Memphis, TN; Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN.
2
Developmental Neurobiology, St. Jude Children׳s Research Hospital, Memphis, TN; Integrated Biomedical Sciences Program, University of Tennessee Health Science Center, Memphis, TN. Electronic address: Suzanne.Baker@stjude.org.

Abstract

Advances in understanding pediatric high-grade glioma (pHGG) genetics have revealed key differences between pHGG and adult HGG and have uncovered unique molecular drivers among subgroups within pHGG. The 3 core adult HGG pathways, the receptor tyrosine kinase-Ras-phosphatidylinositide 3-kinase, p53, and retinoblastoma networks, are also disrupted in pHGG, but they exhibit a different spectrum of effectors targeted by mutation. There are also similarities and differences in the genomic landscape of diffuse intrinsic pontine glioma (DIPG) and pediatric nonbrainstem (pNBS)-HGG. In 2012, histone H3 mutations were identified in nearly 80% of DIPGs and ~35% of pNBS-HGG. These were the first reports of histone mutations in human cancer, implicating novel biology in pediatric gliomagenesis. Additionally, DIPG and midline pNBS-HGG vary in the frequency and specific histone H3 amino acid substitution compared with pNBS-HGGs arising in the cerebral hemispheres, demonstrating a molecular difference among pHGG subgroups. The gene expression signatures as well as DNA methylation signatures of these tumors are also distinctive, reflecting a combination of the driving mutations and the developmental context from which they arise. These data collectively highlight unique selective pressures within the developing brainstem and solidify DIPG as a specific molecular and biological entity among pHGGs. Emerging studies continue to identify novel mutations that distinguish subgroups of pHGG. The molecular heterogeneity among pHGGs will undoubtedly have clinical implications moving forward. The discovery of unique oncogenic drivers is a critical first step in providing patients with appropriate, targeted therapies. Despite these insights, our vantage point has been largely limited to an in-depth analysis of protein coding sequences. Given the clear importance of histone mutations in pHGG, it will be interesting to see how aberrant epigenetic regulation contributes to tumorigenesis in the pediatric context. New mechanistic insights may allow for the identification of distinct vulnerabilities in this devastating spectrum of childhood tumors.

PMID:
25219808
PMCID:
PMC4170681
DOI:
10.1016/j.semradonc.2014.06.003
[Indexed for MEDLINE]
Free PMC Article

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