Other CNS Embryonal Tumors

2023-08-10   Scott Ryall 

1.Brigham and Women's Hospital, Harvard Medical School, Boston , MA (USA)

Classification

Definition

Among embryonal tumors of the central nervous system (CNS), we primarily recognize the relatively common medulloblastoma which, by definition, arise from the cerebellum or dorsal brainstem. However, several rare “other embryonal tumors” which arise across the neuroaxis, are also contained within this group. In the 2021 World Health Organization’s (WHO) classification of CNS tumors, these “other embryonal tumors” include: i) atypical teratoid/rhabdoid tumor (AT/RT), ii) embryonal tumor with multilayered rosettes (ETMR), iii) CNS neuroblastoma, FOXR2-activated, iv) CNS tumor with BCOR internal tandem duplication, and v) CNS embryonal tumor NEC/NOS. 1 Previously, many of these entities were considered “CNS primitive neuroectodermal tumors (PNET),” a classification that has since been retired due to an increased understanding of the tumor's biology and molecular features. 2,3

Other Embryonal Tumors Genetic Event(s)
Atypical teratoid/rhabdoid tumorAtypical teratoid/rhabdoid tumor (AT/RT) are genetically defined by somatic/germline mutations or losses of SMARCB1, a component of the SWI/SNF complex which functions to remodel chromatin. 4-6 Other than recurrent SMARCB1 alterations, which arise in up to 95% of cases, AT/RT have remarkably quiet genomes. 7-10 In the rare instances where a histoloigcally-defined AT/RT lacks a SMARCB1 alteration, they instead harbor biallelic inactivation of SMARCA4, another SWI/SNF complex component. 11,12 Epigenetic and transcriptional profiling have seprated AT/RT into 3 distinct molecular subgroups: i) AT/RT-TYR, ii)AT/RT-SHH, and iii) AT/RT-MYC. 9,10,13,14 The AT/RT-SHH subgroup comprises ~45% of AT/RTs and are characterized by overexpression of proteins within the SHH- and NOTCH-signalling pathways. Approximately 2/3 are infratentorial, the median age at diangosis is 1.8 year, and they frequently harbor compound heterozygous SMARCB1 point mutations. 9,10,13,15. AT/RT-TYR tumors comprise ~35% of AT/RTs and are defined by upregulation of proteins in the melanosomal and BMP pathways in addition to development-related transcription factors, such as OTX2. These tumors are primarily infratentorial, present at a median age of 1 year, and have SMARCB1 inactivation as a result of a mutation in one allele and whole or partial chromosome 22 loss to remove the second. 9,10,13,15 The least common AT/RT subgroup, comprising ~20% of cases are AT/RT-MYC. These tumors are characterized by expression of MYC and HOXC cluster genes and are more commonly supratentorial, although rare spinal and sellar AT/RTs are generally included within this subgroup. 16 Patients with AT/RT-MYC are typically older than those in the other subgroups (median age: ~2 years). 9,10,13,15
Cribriform neuroepithelial tumorCribriform neuroepithelial tumor (CRINET) are defined by bi-allelic alterations impacting SMARCB1. Typically these are losses on chromosome 22q including SMARCB1 co-occuring with SMARCB1 mutations, deletions of exons 7 and 8, or duplications of exon 6. 17-19 DNA methylation analysis classifies CRINET within the AT/RT-TYR subgroup, suggesting overlapping epigenetic and/or transcriptional dysregulation 14,19
Embryonal tumor with multilayered rosettesEmbryonal tumors with multilayered rosettes (ETMR) most commonly (~90%) harbor alterations of a microRNA cluster on chromosome 19q13.42 (C19MC) which includes high-level amplifications, fusions to TTYH1, and other rare gene rearrangements such as fusions to MYO9B or MIRLET7BHG. Ultimately, all of these events result in strong upregulation of the C19MC microRNA cluster as the tumor driving event. 20,21 Rarely, ETMR arise in the setting of DICER1 syndrome OMIM:606241 in which a germline mutation in DICER1 co-occurs with a second mutation in the hotspot RNase IIIb domain. 22,23 Rare ETMRs lacking a C19MC or DICER1 alteration may harbor amplification of the miR-17–92 microRNA cluster on chromosome 13. 23 Other recurrently mutated genes in ETMR include CTNNB1 and TP53. 21 Relapsed ETMR often acquire additional copy-number aberrations including 6q loss and gains of 1q or 17q and an overall increase in chromosomal instability accompanied by a large increase in mutational burden. 21
CNS neuroblastoma, FOXR2-activatedThese tumors are characterized by complex structural rearrangements that converge on FOXR2, an oncogenic transcription factor located on the X chromosome. These structural arrangements result in a fusion between the entire FOXR2 gene and different gene partners and result in elevated FOXR2 expression, likely via enhancer hijacking. 2,24-26 DNA methylation profiling segregates FOXR2-activated neuroblastoma into its own classification and can be reliably used to diagnose these tumors. 2,14
CNS tumor with BCOR internal tandem duplicationThese tumors are defined by a somatic internal tandem duplication (ITD) in BCOR resulting in increased expression and activation of the WNT signaling pathway. 2 The BCOR ITD is often the solitary genetic event in the tumor and is mutually exclusive with other common CNS tumor drivers. In rare instances, additional activating genetic alterations in EP300, SMARCA2, STAG2, and BCORL1 have been reported. 27 Epigenetic and transcriptomic profiling successfully classify these tumors and can be used to reliably differentiate them from other CNS lesions. 2,14
CNS embryonal tumor NEC/NOSCNS embryonal tumor NEC/NOS is the classification used to describe a tumor with morphology consistent with other embryonal tumors, but lacking further molecular features to permit a more specific classification (not elsewhere classified, NEC) or failed a complete molecular workup (not otherwise specified, NOS). The former includes newly identified molecular events that, at this time, lack sufficient data for further diagnostic refinement.

Bibliography

Reference NumberPubmed IDLast YearTitleAuthors

Citation

Scott Ryall

Other CNS Embryonal Tumors

Atlas Genet Cytogenet Oncol Haematol. 2023-08-10

Online version: http://atlasgeneticsoncology.org/solid-tumor/209202