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.