Embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma, and medulloepithelioma share molecular similarity and comprise a single clinicopathological entity

Abstract

Three histological variants are known within the family of embryonal rosette-forming neuroepithelial brain tumors. These include embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma (EBL), and medulloepithelioma (MEPL). In this study, we performed a comprehensive clinical, pathological, and molecular analysis of 97 cases of these rare brain neoplasms, including genome-wide DNA methylation and copy number profiling of 41 tumors. We identified uniform molecular signatures in all tumors irrespective of histological patterns, indicating that ETANTR, EBL, and MEPL comprise a single biological entity. As such, future WHO classification schemes should consider lumping these variants into a single diagnostic category, such as embryonal tumor with multilayered rosettes (ETMR). We recommend combined LIN28A immunohistochemistry and FISH analysis of the 19q13.42 locus for molecular diagnosis of this tumor category. Recognition of this distinct pediatric brain tumor entity based on the fact that the three histological variants are molecularly and clinically uniform will help to distinguish ETMR from other embryonal CNS tumors and to better understand the biology of these highly aggressive and therapy-resistant pediatric CNS malignancies, possibly leading to alternate treatment strategies.

DNMTs as potential therapeutic targets in high-risk pediatric embryonal brain tumors

“…Notably, we and others have identified a subtype of CNS-PNETs (which we call Group 1 CNS-PNETs) distinguished by hallmark genomic amplification of the embryonic stem cell (ES)-enriched C19MC oncogenic miRNA cluster and histological features reminiscent of very early neural differentiation [3,4]. Significantly in recent studies, we observed C19MC amplification in CNS-PNETs with different histologic diagnostic labels, including ETANTRs, ependymoblastoma and medulloepithelioma, originating in various CNS locations [5,6]. These Group 1 tumors collectively comprise~25% of all CNS-PNETs arising in very young children (> 80% are < 4 years old), and are distinctly lethal tumors with characteristic rapid disease tempo.…”

“…Notably, recent studies demonstrate C19MC-associated Group 1 tumors with various histologic labels and anatomic location exhibit a common transcriptional and epigenomic signature, distinct from that of other CNS-PNETs, thus indicating these tumors comprise a common molecular disease [5,6]. Consistent with their distinctly primitive histology, transcriptional signatures of C19MC-associated tumors show most remarkable enrichment of pluripotency and early neural differentiation genes.…”

“…Genetic alterations of DNMTs remain to be identified in brain tumors; however, substantial evidence suggests deregulation of DNMTs that function in maintaining and establishing de novo DNA methylation also contributes to pediatric brain tumor pathogenesis. Subgroups of CNS-PNETs exhibit highly distinct DNA methylation patterns thus suggesting epigenomic mechanisms may also be important in these embryonal tumors [5,6]. Indeed, recent RNA-sequencing studies revealed recurrent gene fusions of C19MC with TTYH1, a developmentally restricted chloride channel gene, associated with very high expression of some C19MC miRNAs and a neural-specific DNMT3B isoform in Group 1 tumors, due to C19MC-mediated targeting of RBL2, a transcriptional repressor of DNMT3B [14].…”

Malignant brainstem tumors in children, excluding diffuse intrinsic pontine gliomas

“…3 ETANTR is an aggressive variant of CNS-PNET characterized by the presence of primitive tumor cells with a small-cell phenotype, abundant neuropil, and ependymoblastic rosettes. 26 The tumor is characterized by a specific amplicon of a microRNA locus on chromosome 19 (C19MC). 26 Interestingly, we also identified a patient with a Wnt-medulloblastoma in the brainstem, which is distinct from fourth ventricular medulloblastomas with brainstem invasion (Fig.…”

“…26 The tumor is characterized by a specific amplicon of a microRNA locus on chromosome 19 (C19MC). 26 Interestingly, we also identified a patient with a Wnt-medulloblastoma in the brainstem, which is distinct from fourth ventricular medulloblastomas with brainstem invasion (Fig. 5).…”