The Genetic Signatures of Pediatric High-Grade Glioma: No Longer a One-Act Play

Abstract

Advances in understanding pediatric high-grade glioma (pHGG) genetics have revealed key differences between pediatric and adult high-grade gliomas (aHGGs), and have uncovered unique molecular drivers among subgroups within pHGG. The three core aHGG pathways, the receptor tyrosine kinase(RTK)/Ras/Phosphatidylinositide 3-kinase (PI3K), p53, and retinoblastoma (RB) 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 non-brainstem high-grade glioma (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 to 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 also carry distinctive signatures, 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.

Common mutations in ALK2/ACVR1, a multi-faceted receptor, have roles in distinct pediatric musculoskeletal and neural orphan disorders

“…Mutations in the same codon were also found in the histone H3.1 gene ( HIST1H3B ) with a frequency of about 20% of cases. Although comparisons of different cohorts of pHGG and DIPG patients revealed some slight differences in the frequency of H3F3A versus HIST1H3B mutations, the H3.1 mutations were more characteristic of younger children and were largely restricted to DIPG (102–104). Both H3.3 and H3.1 mutations are thought to have a dominant-negative effect on the total histone H3 pool and lead to DNA hypomethylation by inhibition of the H3K27 methylase EZH2 and broad changes in gene expression (105).…”

“…Somatic heterozygous mutations in histone H3 isoforms, which characterize pediatric high grade gliomas (pHGGs), were found to be more frequent in DIPG tumors, with the specific missense K27M mutation in H3F3A seen in about 60% of the cases (102, 103). Mutations in the same codon were also found in the histone H3.1 gene ( HIST1H3B ) with a frequency of about 20% of cases.…”

NKG2D ligand expression in pediatric brain tumors

“…Despite fundamental differences between adult and pediatric brain tumors, [66][67][68] children often receive the same treatment modality as adults, which most frequently includes maximal surgical resection, radiation, steroids to reduce inflammation, and chemotherapy. 69 One reason for this is the assumption that pediatric brain tumors establish a microenvironment that supports tumor immune escape.…”

Invited Review: Emerging functions of histone H3 mutations in paediatric diffuse high‐grade gliomas

“…Mouse models created by multiple laboratories using various methodologies have thus far failed to generate tumours using H3K27M alone as a driver ; however, multiple relevant tumour models have now been generated using combinations of oncogenic drivers. PDGFRA is the most frequently altered receptor tyrosine kinase in DIPG, targeted by focal amplification (30%) and/or activating mutation (5%) , and p53 loss of function is seen in 40–50% of DIPGs making these genes the most commonly chosen co‐drivers for these models . The details of these H3K27M mouse tumour models are laid out below.…”