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Gliomas in the Brains of Children

This page was last updated on April 8th, 2024

Childhood gliomas encompass a heterogeneous group of tumors that include low-grade and high-grade tumors. Classification of pediatric gliomas on histology can be challenging. Therefore, identification of specific tumor markers or gene expression signatures such as in medulloblastomas may help to clarify diagnosis and stratify patients into appropriate treatment regimens. Comparative analysis of HGGs and LGGs by DNA hybridization has revealed the relative lack of large chromosomal aberrations in low-grade lesions. However, recognition of chromosome 7 gain in JPA has led to the identification of two candidate oncogenes, BRAF and HIPK2, whose expression is increased in these tumors. Duplication of 7q34 is specific to sporadic (non-NF1-associated) JPAs and is most commonly observed in JPAs in cerebellar and optic pathway/hypothalamic locations (141). The unique feature of certain pediatric LGGs to spontaneously regress has been related to the failure of telomere length maintenance (142). Telomeres are repetitive sequences at the end of chromosomes that shorten with repeated cellular division. Once a critical length is reached, cellular division is stopped by a process termed senescence. The length of telomeres in rapidly dividing cells is maintained by the human telomerase enzyme (hTERT), and hTERT activation is an important feature of aggressive tumors. In fact, hTERT expression is the strongest independent predictor of reduced progression-free and overall survival rates in children with intracranial ependymomas (143). Inhibitors of hTERT have been proposed as viable therapeutics for the treatment of multiple hTERT-expressing tumors.

A number of molecular differences exist between adult and pediatric HGGs, which along with the poor response to radiation and chemotherapy observed in pediatric HGGs, point to biologically distinct tumors. Characterization of the unique features of pediatric HGGs will be critical to understanding the origin of this disease and the development of effective therapies. Pediatric HGGs express fewer known tumor antigens than adult GBMs, suggesting that the immune response in children with pediatric HGGs may be quite different than that in adults (150). Comparative genetic analysis of a large sample of pediatric HGGs has revealed important differences between pediatric and adult tumors in regions of chromosome loss and gain with no significant difference in copy number imbalances (151). Pediatric HGGs are characterized by frequent gain of chromosome 1q and very few chromosome 7 gains or 10 losses. While adult HGGs have frequent EGFR gene amplification, pediatric HGGs have a very low frequency of EGFR amplification (~8%) and instead demonstrate frequent PDGFRA gene amplification (147). Furthermore, IDH1 mutations, which occur at codon 132 in up to 85% of secondary GBMs, were exceptionally absent in the set of pediatric HGGs studied (151). The finding of overexpressed PDGFR-α in pediatric HGGs is of potential therapeutic importance and may also provide insights into the cell of origin of pediatric HGGs.  PDGFR-α is a member of the receptor tyrosine kinase family of cell surface receptor, which also includes PDGFR-β and VEGF receptors. The ligands for PDGFR-α are PDGF AA, AB, and BB. Upon ligand binding the receptor dimerizes, which allows autophosphorylation to take place on intracellular tyrosine residues (153). These phosphorylated residues provide a docking site for downstream signaling molecules (154). Activation of the PDGFR-α can affect cellular function through multiple well characterized signaling pathways including Src-dependent induction of c-MYC, Ras-MAP kinase transcriptional activation, activation of phospholipase C gamma, and activation of phosphatidylinositol 3-kinase (PI3K) downstream effectors (155). Induction of Akt pathway signaling, a PI3K effector, can result in the inhibition of the tuberous sclerosis protein complex (TSC1/2), which in the active state acts to suppress the growth-promoting function of mammalian target of rapamycin (mTOR) (156). Germline loss of function mutations in TSC1 and TSC2 are seen in patients with tuberous sclerosis, who are known to develop subependymal giant cell astrocytomas (SEGAs). Neural stem cells (B cells) in the subventricular zone of adult mice express PDGFR-α and form hyperplasias with cellular atypia and nuclear pleomorphism reminiscent of low and intermediate grade gliomas when stimulated by ligand (157). Thus, it appears that PDGFR-α signaling is important for establishing tumorigenic potential in subventricular zone stem cells, and this mechanism may be contributing to the origins of SEGAs and pediatric high-grade astrocytomas.

In the spectrum of pediatric HGGs there is also variation in gene expression such that subgroups may be established. It has been recognized that a small subgroup of these tumors may be quite similar to adult GBMs (151). However, the majority differ from the adult tumors. Two subsets of childhood malignant gliomas in a sample of 32 tumors could be distinguished when their gene expression was compared to that of adult tumors. One of these groups had increased Ras and Akt pathway activity as well as increased expression of genes driving proliferation and neural stem cell phenotype markers, while the other group did not show Ras and Akt activation. Both groups showed increased expression of Y-box 1 gene, which is a putative oncogene located on chromosome 1p34 (152). Activation of Ras is found in about one-third of human cancers (158) and is thought to be the critical determinant of oncogenesis in patients with NF1. Ras is activated by guanine nucleotide exchange factors (GEFs),which stimulate the exchange of GDP for GTP, and is inactivated by GTPase-activating proteins (GAPs), which stimulate GTP hydrolysis (158). Neurofibromin, which is encoded by the NF1 gene located on chromosome 17q11.2, is highly expressed throughout the CNS (159) and functions as a Ras GAP. Patients with NF1 commonly carry a mutation in one of the two NF1 alleles that results in truncated protein (160). Subsequent mutation in the wild-type allele results in complete loss of neurofibromin function, eliminating the negative regulation of Ras signaling. Activated Ras signals a number of downstream pathways including the PI3K/Akt/mTOR pathway and the Raf-MAK/MEK/ERK pathway, stimulating proliferation and inhibiting apoptosis (161). Individuals with NF1 develop LGGs of the optic pathways, which can regress spontaneously in most cases. Studies of the effects of absent neurofibromin in the CNS of mutant mice shows that glial progenitor cell proliferation is increased, leading to hyperplastic lesions and optic pathway glioma formation (164). The development of HGGs in patients with NF1 may involve more than just loss of neurofibromin function, inasmuch as inactivation of p53 in the setting of NF1 loss leads to glioblastoma formation in mice.

As is the case for ependymomas arising in different locations in the CNS, a unique genetic character is observed for diffuse intrinsic pontine gliomas (DIPGs) when compared to supratentorial W.H.O. grades II and III astrocytomas. High-grade astrocytomas show more frequent losses in chromosomes 9q and 4p, while DIPGs have more frequent losses in 11p, 17p, 14q, 18p, and 22q (166). Hemizygosity at the TP53 gene on chromosome 17p in 7 of 11 DIPGs compared to only 2 of 11 high-grade astrocytomas (166) suggests a potential explanation for the relative radioresistance of DIPGs, as the gene product p53 is key for DNA damage response signaling. Genetic analysis of copy number in DIPGs has also identified two proposed therapeutic molecular targets: PDGFR-α and poly (ADP ribose) polymerase inhibition (166). All 11 DIPGs studied expressed PDGFR-α, and activation of its downstream signaling pathway was suggested by immunohistochemical detection of phosphorylated mTOR protein (166). Thus, the use of receptor tyrosine kinase inhibitors could be considered in future chemotherapeutic trials for the treatment of DIPGs. Gain of the PARP-1 gene was found in 3 of 11 DIPGs, and PARP was expressed in 6 DIPGs (166). PARP is involved in signaling DNA repair of single-stranded breaks, thereby avoiding induction of apoptosis (167). Inhibition of PARP concurrent with alkylating chemotherapeutic agents or ionizing radiation has been proposed for the treatment of malignant gliomas and could be considered for DIPGs in which PARP is active (168). However, the use of PARP inhibitors in tumors with the potential for acquired loss of function in p53 such as DIPGs with hemizygosity at TP53 should be viewed with caution as it has been shown that PARP deficiency in the absence of p53 results in telomere lengthening and enhanced tumorigenesis.