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Review
. 2020 Dec 17;21(24):9654.
doi: 10.3390/ijms21249654.

Hemispherical Pediatric High-Grade Glioma: Molecular Basis and Therapeutic Opportunities

Santiago Haase  1   2 , Fernando M Nuñez  1   2 , Jessica C Gauss  1   2 , Sarah Thompson  1   2 , Emily Brumley  1   2 , Pedro Lowenstein  1   2 , Maria G Castro  1   2
Affiliations
Review

Hemispherical Pediatric High-Grade Glioma: Molecular Basis and Therapeutic Opportunities

Santiago Haase et al. Int J Mol Sci. .

Abstract

In this review, we discuss the molecular characteristics, development, evolution, and therapeutic perspectives for pediatric high-grade glioma (pHGG) arising in cerebral hemispheres. Recently, the understanding of biology of pHGG experienced a revolution with discoveries arising from genomic and epigenomic high-throughput profiling techniques. These findings led to identification of prevalent molecular alterations in pHGG and revealed a strong connection between epigenetic dysregulation and pHGG development. Although we are only beginning to unravel the molecular biology underlying pHGG, there is a desperate need to develop therapies that would improve the outcome of pHGG patients, as current therapies do not elicit significant improvement in median survival for this patient population. We explore the molecular and cell biology and clinical state-of-the-art of pediatric high-grade gliomas (pHGGs) arising in cerebral hemispheres. We discuss the role of driving mutations, with a special consideration of the role of epigenetic-disrupting mutations. We will also discuss the possibilities of targeting unique molecular vulnerabilities of hemispherical pHGG to design innovative tailored therapies.

Keywords: ATRX; G34R; HGG; cancer; epigenetics; hemispheric pHGG; pHGG; pediatric high-grade glioma.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Illustration depicting the main pathways altered in hemispheric pediatric high-grade gliomas (pHGG): The main genetic alteration associated with pathways alterations are indicated.
Figure 2
Figure 2
Illustration depicting the most prominent epigenetic alterations in hemispheric pediatric high grade glioma (pHGG): The most common epigenetic alterations are H3F3A-G34R/V (Glycine to Arginine or Valine mutations in Histone H3.3) mutations and ATRX (thalassemia/mental retardation syndrome X-linked) loss-of-function mutations. Less frequently, mutations on SET Domain Containing 2 protein (SETD2), an H3K36me3 writer, Death domain-associated protein (DAXX), part of the ATRX/DAXX complex, and Isocitrate dehydrogenase 1 (IDH1), among others, also act as epigenetic disruptors. IDH1 gain of function mutations lead to the production of 2-hydroxyglutarate (2-HG), which inhibits histone and DNA demethylases.
Figure 3
Figure 3
Scheme depicting the molecular classification of hemispherical pHGG, indicating the main molecular subgroups and the common mutations, genetic alterations, transcriptional programs, global, and O-6-Methylguanine-DNA Methyltransferase (MGMT) methylation status, and the clinical characteristics (included anatomical location in the upper brain illustration) associated to each molecular subgroup.
See this image and copyright information in PMC

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