Classification and Treatment of Pediatric Gliomas in the Molecular Era

Abstract

The overall survival of pediatric gliomas varies over a wide spectrum depending on the tumor grade. Low-grade gliomas have an excellent long-term survival, with a possible burden of surgery, irradiation, and chemotherapy; in contrast, high-grade gliomas generally have a short-term, devastating lethal outcome. Recent advances in understanding their molecular background will transform the classification and therapeutic approaches of pediatric gliomas. Molecularly targeted treatments may acquire a leading role in the primary treatment of low-grade gliomas and may provide alternative therapeutic strategies for high-grade glioma cases in the attempt to avoid the highly unsuccessful conventional therapeutic approaches. This review aims to overview this progress.

Bevacizumab in the Treatment of Refractory Brain Edema in High-grade Glioma

“…3 Other targeted therapeutics in case of specific molecular abnormalities in the tumors have been increasingly used, especially considering the extremely poor prognosis of these patients. 4 One typical finding in these malignant tumors is the presence of peritumoral edema which contributes significantly to the mass effect of these neoplasms and results in neurological deterioration, increased intracranial pressure, and focal neurological deficits. In glioma, vasogenic peritumoral edema is thought to be a result of blood-brain barrier disruption leading to increased vascular permeability and the flow of fluid, and proteins into extracellular space.…”

Aberrant DNA repair is a vulnerability in histone H3.3-mutant brain tumors

“…The K27M mutation is also found in the H3.1 histone variant (H3.1 K27M) in some pHGG and inhibits NHEJ in human fibroblasts (Zhang et al, 2018), which is opposite to the phenotype of H3.3 K27M in U2OS cells. Although a true comparison requires that the H3.1 K27M and H3.3 K27M phenotypes be studied in the same cellular background, differences in their DNA repair function can be anticipated since they show distinct distribution patterns in chromatin (Sarthy et al, 2020), present different co-occurring mutations (Hauser, 2021; Mackay et al, 2017) and clinical features in pHGG (Castel et al, 2015; Werbrouck et al, 2019).…”

The Transcriptomic Landscape of Pediatric Astrocytoma

“…In pediatric tumors, driver mutations in IDH1/2 are rare; instead they harbor specific recurrent mutations in the genes encoding H3.3 ( H3F3A ) and H3.1 ( HIST1H3B , HIST1H3C ) histone variants, resulting in amino acid substitutions in two key residues in the histone tail: lysine-to-methionine at position 27 (K27M) and glycine-to-arginine or -valine at position 34 (G34R/V) [ 42 , 43 ]. Currently, the genetics and epigenetics of pHGA harboring mutations in IDH1/2 and H3F3A are under intensive study [ 3 , 21 , 42 , 44 ]. In our experimental setup, we had pediatric high-grade cerebellum and cerebrum astrocytoma without mutations in IDH1/2 and H3F3A .…”