Fig. 7.1
Summary of molecular subgroups and recurrent genomic alterations identified in pediatric brain tumors
Integrated genomic studies have revealed that MB comprises at least four molecular variants, which are genetically and clinically distinct. These four subgroups are termed WNT, Sonic Hedgehog (SHH), Group 3, and Group 4 [1] have significant prognostic value, and can be further subdivided into additional relevant molecular subtypes. The delineation of these four core subgroups underscores the heterogeneity that exists between MB patients. The WNT subgroup is characterized by activation of the WNT pathway, which commonly harbors mutations in β-catenin (CTNNB1). Patients with WNT activated tumors tend to have a favorable prognosis and occur primarily outside the infant age group. The SHH subgroup is characterized by activation of the Sonic Hedgehog (SHH) pathway and is more common in infants with desmoplastic tumors and in adults. Group 3 MBs have a poor prognosis and are commonly associated with metastatic disease. MYC amplification is common in Group 3 MBs, and survival in these patients is poor. Group 4 MBs have an intermediate prognosis and are commonly associated with isochromosome 17q and MYCN amplification.
There have been a number of chromosomal alterations reported in MB. The most commonly reported cytogenetic abnormality is isochromosome 17q (i17q), involving the loss of chromosome 17p and gain of 17q, which is found in 30–40 % of all primary MB tumors. This is also a genomic feature of the Group 4 subgroup, which is observed in more than 80 % of cases. Other less common aberrations include gains on chromosomes 1q, 3q, 7, and 17q, as well as loss on chromosome 5q, 9q, 10q, 11, 17p, and 22 [2].
Recent publications highlight the importance of examining the mutational landscape of MB according to subgroup affiliation [3, 4]. WNT subgroup MBs remain the most genomically balanced of the four subgroups without any focal recurrent somatic copy number alterations (SCNAs). The most common mutation observed in this subset is in CTNNB1, which highlights the important role of WNT signaling in this subgroup, and less frequently in DDX3X. Many groups have sought to identify the cell of origin for this subgroup. It has been suggested to be the progenitor cells of the lower rhombic lip. Further, a mouse model harboring activated Ctnnb1 in the Blbp expressing radial glial cells has been shown to generate MBs that are characteristic of WNT tumors [5].
SHH subgroup is the best characterized of the four subgroups, with the distinctive feature of activated SHH signaling. Somatic mutations targeting the SHH receptor PTCH1 and downstream genes, such as SUFU, are found exclusively in this subgroup. SCNAs targeting the PI3K signaling cascade have also been known to be aberrant in this subgroup. Most animal models of SHH MBs involve the inactivation of patched1 in either the cerebellar granule neuron precursors (CGNP; marked by Atoh1) or neural stem cells (NSC; marked by GFAP) [6].
Group 3 and 4 MBs are currently the least understood. Group 3 MB is associated with the worst prognosis and characterized by high-level amplification of the proto-oncogene MYC. Research examining somatic mutations have identified dysregulation of the epigenome in both Group 3 and 4 MBs. These events, although occurring across all MBs, are enriched in chromatin-associated genes such as MLL2, MLL3, SMARCA4, and KDM6A. These newly identified mutations point to the importance of the chromatin structure in MB pathogenesis. Efforts have also identified novel fusion proteins such as PVT1–MYC and novel mechanisms such as the tandem duplication of SNCAIP in Group 3 and 4 MBs, respectively. The biological and clinical relevance of these novel pathogenic mechanisms will need to be further studied. Although no transgenic models of Group 3 and 4 diseases exist, several orthotopic transplantation models are currently being studied. The activation of Myc with p53 inactivation generates medulloblastomas with characteristic Group 3 features [7].
Pediatric High-Grade Glioma
Pediatric Glioblastoma
Whole-exome sequencing of pediatric glioblastoma (GBM) cases has revealed somatic recurrent mutations in a gene called H3F3A, which encodes a replication-independent histone variant H3.3 [2] (Fig. 7.1). Heterozygous mutations in H3F3A are present in 31 % of pediatric GBMs and result in amino acid substitutions within the N-terminal histone tail, specifically a lysine to methionine (K27M), a glycine to arginine (G34R), or a glycine to valine (G34V) substitution [2]. These mutations, which occur specifically in pediatric GBMs, and often with TP53 mutations (54 % of cases), are situated at sites which are important for post-translational modification of histone 3 (H3) and regulation of global chromatin structure. Recurrent mutations in ATRX and DAXX have also been reported in 31 % of pediatric GBMs and present always in tumors harboring a G34R/V mutation [2]. The ATRX and DAXX proteins are important for H3.3 incorporation at peri-centrometic heterochromatin and telomeres [2]. Together somatic mutations in the H3.3-ATRX-DAXX chromatin remodeling pathway have been identified in 44 % of pediatric GBMs [2]. Epigenomic differences between subsets of pediatric GBM patients were demonstrated in a study examining DNA methylation signatures in a series of 59 childhood and 77 adult GBM patients [8]. Here they identified robust, epigenetically distinct subgroups defined by GBM mutations and gene expression-defined classes. The subgroups were classified as: (1) IDH1 mutated (adults), (2) H3.3-K27 mutated, (3) H3.3-G34 mutated, (4) RTKI (PDGFRα amplified, proneural), (5) mesenchymal, and (6) RTKII (classic). Copy number events also defined subgroups of pediatric GBM, specifically PDGFRα amplifications in the RTKI subgroup, whole chromosome 7 gains, chromosome 10 loss, CDKN2A homozygous deletions, and EGFR amplifications in RTKII pediatric GBMs [8]. Additional copy number events have been observed in comprehensive copy number studies of high-grade gliomas, including chromosome 8p12 loss in ~16 % of cases, encompassing a potential tumor suppressor gene, ADAM3A, MYCN amplifications (5 %), and chromosome 1q gain [9].
Diffuse Intrinsic Pontine Glioma
The vast majority (up to 78 %) of diffuse intrinsic pontine gliomas (DIPGs) harbors heterozygous H3.3-K27M mutations [10] (Fig. 7.1). TP53 mutations have also been observed in up to 77 % of patients and are often concurrent with H3F3A mutations, PDGFRA gene amplifications, and MYC–PVT1 gene fusions. ATRX mutations have also been reported in older DIPG patients, albeit at lower frequency (9 %), further highlighting aberrant chromatin structure in DIPG patients. The copy number landscape of DIPGs pinpoints other pathways relevant to disease formation, namely the PI3K pathway which is affected in ~47 % of DIPGs, involving PDGFRa, MET, IGF1R, ERRB4, EGFR, KRAS, AKT1, AKT3, and PIK3CA focal gains [11]. Gross copy number events have also reported to be enriched in DIPGs, specifically gains of chromosomes 2q, 8q, and 9q and losses of 16q, 17p, and 20p [11].
Pediatric Low-Grade Glioma
Non-diffuse Low-Grade Glioma: Pilocytic Astrocytomas
Spontaneous pilocytic astrocytomas (PAs) occur typically in the cerebellum, and in the absence of NF1 mutations. The most common genetic alteration in spontaneous PAs results in increased activity of the MAPK pathway, through a tandem duplication event on chromosome 7q34, which forms an in-frame fusion of KIAA1549 with BRAF [12] (Fig. 7.1). Adding to this, genome sequencing studies of low-grade gliomas have shown that the MAPK pathway is affected in nearly all tumors and that PAs may represent a single pathway-driven disease [13]. Several other, albeit less frequent, genetic alterations convergent upon BRAF activation have been reported including FAM131B–BRAF, RNF130-BRAF, CLCN6–BRAF, MKRN1–BRAF, and GNAI1–BRAF fusions, all of which result in N-terminal loss of the BRAF regulatory region [13]. The significance of BRAF alterations is further highlighted by the presence of somatic mutations. These findings are supported functionally, in which PAs are generated by ectopic activation of BRAF in murine neural progenitor cells [14]. Recurrent, somatic, and activating mutations in PAs have also been identified at lower frequencies in other genes such as KRAS, FGFR1, PTPN11, and NTRK2 fusions, however all of which lead to downstream MAPK activation [13].
Diffuse Low–Grade Glioma: Diffuse Grade II Astrocytomas, Ganglioglioma, Angiocentric Glioma, and Pleomorphic Xanthoastrocytoma
Diffuse low-grade gliomas are also affected by BRAF alterations; however, these occur mostly in the setting of BRAF–V600E mutations [15]. In the case of diffuse Grade II gliomas, recurrent amplifications of MYC and intragenic duplications of FGFR1 have been reported, and shown to be largely mutually exclusive [16]. Copy number profiling in diffuse Grade II gliomas has identified other candidates, such as a partial duplication of the MYBL1 transcription factor in 28 % of cases, which results in loss of its C-terminus negative regulatory domain [17]. In the same pathway, MYB amplifications have also been observed at lower frequency, in addition to deletion-truncation breakpoints in the regulatory terminus of MYB, seen preferentially in angiocentric gliomas [17]. Loss of chromosome 9, encompassing the CDKN2A/p14ARF/CDKN2B locus, has been reported in ~50 % of pleomorphic xanthoastrocytomas, along with less frequent loss of chromosome 17 [18].
Desmoplastic Infantile Astrocytomas/Ganglioglioma
Desmoplastic infantile astrocytomas (DIA)/gangliogliomas (DIG) displayed only a few nonrecurrent genomic imbalances or normal karyotypes. Only loss of chromosome 9p and 22q was recurrently observed in a limited number of studies to date [19]. Characteristic genomic imbalances were not observed when DIA were compared with DIG [19]. BRAF V600E mutation, EGFR and MYCN amplification have been described in single cases.
Central Nervous System Germ Cell Tumors
Several studies have investigated cytogenetic alterations in central nervous system germ cell tumors (CNS-GCTs). A study of 15 malignant CNS-GCTs revealed recurrent gains of 12p12 which is also commonly amplified in adult testicular germ cell tumors [20]. Recurrent gains of 1q and 8q and recurrent losses on chromosome 11, 18, and 13 were also detected. The genomic alterations identified in this series were almost identical to those found in gonadal and extragonadal germ cell tumors. Moreover, there were no differences in the cytogenetic profiles of germinomas compared to non-germinomatous CNS-GCT. This suggests strongly that the pathogenesis of CNS-GCTs is similar to systemic GCTs. At a transcriptional level, there are several differences between germinomas and non-germinomatous germ cell tumors. Genes responsible for self-renewal (OCT4, NANOG, and KLF4) and immune response are more highly expressed in germinomas whereas genes involved in neuronal differentiation, Wnt/β-catenin pathway, invasiveness, and epithelial-mesenchymal transition are more commonly observed in malignant non-germinomatous germ cell tumors. The transcriptional profiles of non-germinomatous germ cell tumors closely resemble the profiles observed in embryonic stem cells consistent with their more undifferentiated nature.
Craniopharyngioma
Craniopharyngiomas are thought to arise from squamous-cell rests along the path of the primitive craniopharyngeal duct and adenohypophysis. The adenohypophysis arises from Rathke’s pouch. As such it is believed that these squamous-cell rests represent the cell of origin for craniopharyngioma, and it is generally felt that adamantinomatous craniopharyngioma represents a developmental anomaly. The rare papillary histological variant more common in adults appears to arise from the adenohypophysis; however, this remains to be confirmed. Recent studies have shown activating mutations in exon 3 of the β-catenin gene (CTNNB1) to be common in adamantinomatous craniopharyngioma suggesting a likely role for Wnt signaling in the pathogenesis of craniopharyngioma [21].
Central Nervous System Primitive Neuroectodermal Tumors
Primitive neuroectodermal tumors of the central nervous system (CNS-PNET) are a heterogeneous group of pediatric neoplasms composed of poorly differentiated neuroepithelial cells with varying degrees of divergent neural, astrocytic, and ependymal differentiation. Using global profiling, Picard et al. (2012) identified that CNS-PNETs comprise three distinct molecular groups: primitive-neural (Group 1), oligoneural (Group 2), and mesenchymal (Group 3) [22] (Fig. 7.1). Group 1 tumors are enriched in primitive-neural genes (CD133, CRABP1, LIN28, and ASCL1) and display activation of SHH and WNT signaling. Group 2 tumors are composed of genes with roles in oligoneural differentiation (OLIG1/2, SOX8/10, and BCAN) and exhibit down-regulation of SHH components. Lastly, Group 3 tumors comprise genes involved in epithelial and mesenchymal differentiation (COL1A2, COL5A, FOXJ1, and MSX1) and display up-regulation of genes involved in TGF-β and PTEN signaling. Copy number analyses reveal that Group 2 tumors have frequent gains of chromosome 8p, 13, and 20, whereas Group 3 have frequent loss of chromosome 14. Also Group 2 and 3 tumors have frequent chromosome 9p loss centered on the CDKN2A/2B locus. In 2000, Eberhart et al. [23] described a new CNS-PNET variant (termed “embryonal tumor with abundant neuropil and true rosettes” or ETANTR), which, based on gene expression profiling, are subgroups with Group 1 CNS-PNETs [22, 24]. Hallmark cytogenetic features of ETANTRs include frequent gains of chromosome 2 and 3, and focal amplification of an miRNA amplicon on chr19q13.41, which encompasses the oncogenic C19MC miRNA cluster [24]. Li et al. (2009) identified that chr19q13.41 amplification characterizes CNS-PNET variants labeled as ETANTRs, medulloepithelioma, supratentorial PNET with ependymal differentiation, and ependymoblastoma, suggesting that these tumors represent closely related molecular entities [24]. Although the mechanisms by which C19MC miRNAs mediate oncogenesis remain unclear, these miRNAs are implicated in cell survival, transformation, activation of noncanonical WNT-JNK2 signaling, and inhibition of differentiation of human neural stem cells [25]. Furthermore, ETANTRs are also distinguished by the presence of distinct primitive markers, including the RNA binding protein, Lin28 [22].
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