Central Nervous System Tumors in Children

WNT Tumors

These tumors are the least common of the four subgroups, occur most frequently in children older than 3 years old and almost always are located in the fourth ventricle or near the brainstem. They have the most favorable prognosis, with 5-year survival rates exceeding 95%. The link between WNT signaling and medulloblastoma was first made in patients with Turcot's syndrome, a hereditary disease caused by mutations in the adenomatous polyposis gene, which functions as a negative regulator of WNT signaling. This syndrome was found to be associated with a higher incidence of medulloblastoma. It was subsequently discovered that subsets of sporadic medulloblastoma harbor WNT signaling pathway mutations, most notably in the CTNNB1 gene, which encodes β-catenin. The WNT signaling pathway is highly conserved in metazoans, and is involved in a diverse range of cellular process, including cell-cycle control, stem cell renewal, and cell motility/polarity.

SHH Tumors

These are a heterogeneous group of tumors, which account for nearly one-third of all medulloblastoma. They are seen most frequently at either ends of the age spectrum (i.e., infants and adults), and they are associated with an intermediate prognosis. A link between the SHH signaling pathway a medulloblastoma was initially recognized in patients with Gorlin's syndrome, which is characterized by craniofacial abnormalities and predisposition to several cancers, including medulloblastoma. Mutations in PTCH1 have been described in Gorlin's patients, which is a negative regulator of the SHH pathway. Subsequent studies linked medulloblastoma to several other key gene mutations or other genetic alterations within the SHH signaling pathway, including SUFU, SMO, SHH, GLI2, and MYCN . The SHH signaling pathway plays a critical role in numerous cellular processes, including cell proliferation, differentiation, and vertebrate organogenesis.

Group 3 Tumors

These tumors account for a quarter of medulloblastomas, are found in younger patients, and are associated with the worst prognosis. Likely because of their location near the fourth ventricle at the midline of the brainstem, cerebrospinal fluid (CSF) metastases are common and frequently seen at the time of initial diagnosis. Although specific mutations are not common in this subgroup, focal somatic copy number aberrations have been described, including amplification of the MYC oncogene.

Group 4 Tumors

Group 4 tumors are the most common subgroup and they share many similarities to group 3 medulloblastoma, including close proximity to the fourth ventricle and frequent metastases at diagnosis. Overall, it is the most poorly understood tumor within the four subgroups from a molecular perspective. Somatic copy number aberrations have been described in this tumor, including duplication of the SNCAIP gene, which encodes a protein implicated in Parkinson's disease.

Central Nervous System Embryonal Tumor Not Otherwise Specified (Formerly Supratentorial Pnets)

These tumors resemble medulloblastoma but differ in their location outside of the posterior fossa in the brain. They are genetically heterogeneous tumors, with some reports of copy number alterations in MYCN , PDGFB and PDGFRA, as well as deletions in CDKN2A/B . More recently, a high-level amplicon involving the chr19q13.41 microRNA cluster (C19MC) was reported in a subset (~25%) of these PNETs. In the 2016 central nervous system (CNS) WHO classification, the presence of C19MC amplification results in the diagnosis of embryonal tumor with multilayered rosettes (ETMR) (PMID: 27157931 ). On the basis of DNA methylation profiling, it has been shown that a significant proportion of institutionally diagnosed CNS-PNET are in fact other well-defined CNS tumor entities (i.e., high-grade glioma), whereas four distinct tumor entities have emerged from the remaining histologically defined CNS-PNETs. This has resulted in removal of the term PNET and addition of the term CNS embryonal tumor, not otherwise specified, in the updated WHO classification.

Supratentorial Tumors

Approximately two-thirds of supratentorial ependymoma harbor fusions between the RELA gene and C11orf95, termed ST-EPN-RELA, which is associated with an extremely poor prognosis. The former gene is involved in NF-κB signaling, and little is known about the function of latter gene. However, emerging preclinical data suggest that RELA fusions are key oncogenic drivers, promote tumor cell invasion, and are associated with resistance to cytotoxic chemotherapies. Of note, the most recent WHO 2016 classification for ependymoma now includes a subcategory for RELA fusion-positive ependymoma. The remaining one-third of supratentorial ependymoma lack RELA fusions, but instead harbor YAP1 fusions, a gene involved in the Hippo signaling pathway. These tumors are termed ST-EPN-YAP1, and emerging data suggest that these tumors are associated with an excellent prognosis.

Posterior Fossa Tumors

Before the aforementioned ependymoma DNA methylation study, two previous studies had already suggested two biologically distinct forms of posterior fossa ependymomas (PF-EPN-A and PF-EPN-B). These two groups demonstrated unique differences with regard to molecular characteristics, patient demographics, and clinical outcomes. PF-EPN-A tumors tend to occur in younger patients, are likely to recur locally, metastasize distantly, and overall are associated with a much poorer prognosis in comparison to PF-EPN-B tumors. At the molecular level, PF-EPN-A tumors are most notable for transcriptional silencing driven by a CpG-island methylator phenotype, which is associated with hyperactivity of the Polycomb Repressive Complex 2 (PRC2).

High-Grade Glioma

As noted previously, pediatric HGGs can be classified into six unique molecular subtypes. The K27 and G34 subgroups are composed of tumors with heterozygous mutations in two key histone genes, H3.3 and H3.1. (also referred to as H3F3A and HIST1H3B/C, respectively), resulting in amino acid substitutions at K27 or G34 . Histone H3 K27M mutations are found in approximately 80% of midline pediatric HGGs, including DIPG, and given the stereotypic location and uniformly poor outcome have been designated as diffuse midline glioma, H3 K27M-mutant tumors in the 2016 CNS WHO classification. This mutation disrupts the PRC2 complex via inhibition of its catalytic subunit, EZH2. This leads to reductions in the overall levels of trimethylated histone H3 marks at the K27 position (H3K27me3), which causes transcriptional de-repression .

In the adult setting, isocitrate IDH1/2 are common in LGGs (>70% tumors) and less frequent in glioblastoma. Early studies had suggested that IDH1/2 mutations were rare in pediatric gliomas (~10% or less), although these were based on the analysis of small case numbers. Because more comprehensive analyses emerged with larger case numbers, and using next-generation sequencing (NGS)-based mutation detection techniques, it has become apparent that IDH1/2 mutations are relatively common in the adolescent and young adult population. For example, a study by the Children's Oncology Group (COG) found IDH1/2 mutations in 35% of children ≥14 years of age, which was corroborated in two NGS-based studies of pediatric gliomas.

Low-Grade Glioma

Pediatric LGGs have been referred to as “genetically quiet,” with few mutations found in these tumors; however, alterations have been reported that appear to converge on the RAS/MAPK pathway. In particular, genetic aberrations in BRAF have been described in pediatric LGGs, including BRAF fusions with KIAA1549, as well as V600E point mutations.

DIPG

H3 K27M mutations are also common in DIPGs (in up to 80% of cases), and frequently co-occur with mutations in the Protein Phosphatase Mg ²⁺ /Mn ²⁺ Dependent 1D (PPM1D) gene. The PPM1D gene encodes a serine/threonine phosphatase that dephosphorylates numerous proteins primarily involved in the DNA damage response and cellular checkpoint pathways. Histone mutations in DIPG are also linked to activating mutations in the activing A receptor type 1 (ACVR1) gene. Interestingly, identical mutations have been reported in the hereditary disease, fibrodysplasia ossificans progressive.