Pediatric gliomas as neurodevelopmental disorders

Abstract

Brain tumors represent the most common solid tumor of childhood, with gliomas comprising the largest fraction of these cancers. Several features distinguish them from their adult counterparts, including their natural history, causative genetic mutations, and brain locations. These unique properties suggest that the cellular and molecular etiologies that underlie their development and maintenance might be different from those that govern adult gliomagenesis and growth. In this review, we discuss the genetic basis for pediatric low-grade and high-grade glioma in the context of developmental neurobiology, and highlight the differences between histologically-similar tumors arising in children and adults.

Keywords: DIPG; diffuse astrocytoma; glioblastoma; pediatric glioma; pilocytic astrocytoma.

Figure 1. Developmental origins of glia in the brain

(A) Ventricular zone stem cells or radial glia (RG) function as the embryonic sources of glial progenitors. Two separate waves of oligodendrocyte progenitor cells (OPCs) arise from specific ventricular zone regions at E12 and E15, and migrate in streams to populate the telencephalon. Radial glia shift from neurogenesis to gliogenesis at E16 to generate intermediate glial progenitors. The majority of gliogenesis occurs during the first 3 weeks postnatally. The predominant source of oligodendrocytes in the postnatal brain comes from a third wave of OPCs that appears in the cortex around birth, expands, and differentiates into myelinating oligodendrocytes. Intermediate glial progenitors migrate into the cortex and differentiate into astrocytes. These differentiated astrocytes also undergo symmetric division during the first three weeks of age. In the adult, differentiated astrocytes can generate additional astrocytes, especially in response to injury. New oligodendrocytes are formed in the adult brain from resident OPCs in the cortex as well as OPCs arising from intermediate progenitors of the subventricular zone.

Figure 2. Low-grade glioma growth control pathways

LGGs arise from mutations in genes whose protein products regulate RAS pathway signaling. In this manner, mutations in genes encoding receptor tyrosine kinases (RTK), which transduce extracellular signals, as well as the downstream effectors PTPN11, RAS, BRAF/RAF, and lead to hyperactivation of mitogenic signaling downstream through the MAP kinase and PI3-kinase pathways. In addition, mutational inactivation of the neurofibromatosis type 1 (NF1) tumor suppressor gene results in increased RAS activity. MEK and AKT can shorten G1 transition through mammalian target of rapamycin (mTOR)-dependent and -independent signaling. The presence of stromal growth factors and chemokines in the tumor microenvironment transduce signals through tumor cell receptors and further enhance glioma growth in a paracrine fashion. Reported mutations are denoted in green.

Figure 3. The glioma ecosystem

Gliomas form and are maintained by a circuit of cellular and acellular elements, including neurons, endothelial cells, and monocytes (microglia and macrophages), which each produce growth factors (neuroligin-3 [NLGN3], vascular endothelial-derived growth factor [VEGF]) and chemokines that stimulate neoplastic glia.

Figure 4. Spatiotemporal association of mutations in pediatric high-grade glioma

Clear associations between specific mutations and age- and location-dependent subgroups of pediatric HGG indicate a strong connection between brain development and gliomagenesis in children. Histone H3 K27M mutations are found predominantly in DIPGs, and other midline HGGs including thalamic and cerebellar (green), with the majority of mutations occurring in the H3.3 isoform. The youngest DIPG patients show a predominance of ACVR1 mutations and K27M mutations in the H3.1 isoform. Histone H3.3 G34R/V mutations are predominantly found in cortical HGGs of late adolescence, most commonly those arising in the parietal, occipital, or temporal lobes (blue). In contrast, frontal lobe HGGs of late adolescence and young adults are more commonly associated with IDH1 R132H mutation (pink). BRAF^V600E mutations and CDKN2A homozygous deletions are found in non-brainstem HGGs and not DIPGs, and NF1 mutations are more frequent in cortical HGGs than DIPG. NTRK fusion genes have been reported in non-brainstem HGGs as well as DIPGs, but appear to occur at higher frequency in HGGs arising outside the brainstem in children less than 3 years of age. FGFR1 mutations are found predominantly in thalamic HGGs. Mutations in TP53, PDGFRA, PIK3CA and PIK3R1 are found in HGGs from all locations.