Early ependymal tumor with MN1-BEND2 fusion: a mostly cerebral tumor of female children with a good prognosis that is distinct from classical astroblastoma

Abstract

Purpose: Review of the clinicopathologic and genetic features of early ependymal tumor with MN1-BEND2 fusion (EET MN1-BEND2), classical astroblastomas, and recently described related pediatric CNS tumors. I also briefly review general mechanisms of gene expression silencing by DNA methylation and chromatin remodeling, and genomic DNA methylation profiling as a powerful new tool for CNS tumor classification.

Methods: Literature review and illustration of tumor histopathologic features and prenatal gene expression timelines.

Results: Astroblastoma, originally descried by Bailey and Cushing in 1926, has been an enigmatic tumor. Whether they are of ependymal or astrocytic derivation was argued for decades. Recent genetic evidence supports existence of both ependymal and astrocytic astroblastoma-like tumors. Studies have shown that tumors exhibiting astroblastoma-like histology can be classified into discrete entities based on their genomic DNA methylation profiles, gene expression, and in some cases, the presence of unique gene fusions. One such tumor, EET MN1-BEND2 occurs mostly in female children, and has an overall very good prognosis with surgical management. It contains a gene fusion comprised of portions of the MN1 gene at chromosomal location 22q12.1 and the BEND2 gene at Xp22.13. Other emerging pediatric CNS tumor entities demonstrating ependymal or astroblastoma-like histological features also harbor gene fusions involving chromosome X, 11q22 and 22q12 breakpoint regions.

Conclusions: Genomic DNA profiling has facilitated discovery of several new CNS tumor entities, however, traditional methods, such as immunohistochemistry, DNA or RNA sequencing, and cytogenetic studies, including fluorescence in situ hybridization, remain necessary for their accurate biological classification and diagnosis.

Keywords: Astroblastoma; Cerebral tumor; Chromatin remodeling; EWSR1-BEND2; Early ependymal tumor with MN1-BEND2 fusion; Female; Genomic DNA methylation; Good prognosis; HGNET BCOR ex15 ITD; MN1-CXXC5; NET-MN1; NET-PATZ1; Pediatric; Supratentorial ependymoma.

Fig. 1

Unsupervised UMAP dimension reduction analysis map of genomic DNA methylation from the DFKZ CNS tumor reference set. The reference set includes methylation data for 2729 tumors (76 pathological diagnoses) and 72 normal brain tissues. Each group of data points represent a specific normal tissue or tumor diagnosis or closely related diagnoses [9]. The arrow indicates HGNET MN1 tumors (consisting mostly of EET MN1-BEND2)

Fig. 2

Typical MR findings of EET MN1-BEND2. T1 post-contrast MR images of EET MN1-BEND2 presenting in a 9-year-old girl. T1 post-contrast axial and sagital images show typical well-demarcated complex solid and cystic appearance of EET MN1-BEND2. Like other supratentorial ependymal tumors, they often show a bubbly and/or multinodular appearance [59]. Images courtesy of Dr. Bret Mobley, Vanderbilt University

Fig. 3

Histopathology of EET MN1-BEND2. A Perivascular pseudorosette in EET MN1-BEND2, B EET MN1-BEND2 papillary growth pattern. C Vascular and stromal sclerosis in EET MN1-BEND2. D EET MN1-BEND2 showing tumor necrosis. E ZFTA-RELA supratentorial ependymoma pseudorosette. F MAPK astroblastoma pseudorosette demonstrating more elongated cells with prominent nucleoli. A multinucleate cell is indicated by the arrow. G EET MN1-BEND2 EMA immunohistochemical stain demonstrating membrane and dot-like cytoplasmic positivity. H ZFTA-RELA supratentorial ependymoma showing similar EMA immunostaining. I and J Scattered GFAP immunostaining in EET MN1-BEND2 and ZFTA-RELA ependymoma, respectively. K Diffuse GFAP staining in MAPK astroblastoma. L MN1 immunohistochemical stain of EET MN1-BEND2 depicting strong nuclear staining. Such staining was absent in MAPK astroblastomas, however the sensitivity and specificity of MN1 immunohistochemical staining for EET MN1-BEND2 is not yet known [10]

Fig. 4

Pediatric supratentorial ependymal tumor genes are highly expressed in the late embryonic/early fetal period and classical astroblastoma associated genes are expressed later during fetal and postnatal gliogenesis. The developmental expression timecourse (in post-conception weeks) of select genes overexpressed or mutated in EET MN1-BEND2 and other pediatric supratentorial ependymomas and MAPK astroblastomas was obtained from the Allen Human Developmental Transcriptome database. Pediatric supratentorial ependymoma and related tumor genes (relatively overexpressed or mutated) are depicted in plain type on the left and MAPK astrocytoma associated genes are in bold on the right. The patient age bar progressive color scheme is arbitrary. Pediatric ependymal tumor associated genes, including MAMLD1, PATZ1, FOXJ1, YAP1, MN1, CXXC5, RELA, EWSR1, BCOR and ZFTA1 are more highly expressed prior to 25 pcw. Some EET MN1-BEND2 associated genes, e.g., CELSR1, DLX5, HES1, FOXJ1, YAP1, SOX1, BCOR and H19, are most highly expressed prior to 10 pcw during the late embryonic/early fetal period. MAPK astrocytoma associated genes are more highly expressed after 25 pcw. Transcript expression is normalized by reads per kilobase of transcript per million mapped reads (RPKM) to compensate for RNA-seq generation of more sequencing reads from longer RNA molecules. Data is from up to 16 brain regions from 42 specimens [Allen Institute for Brain Science. Allen Human Brain Atlas. BrainSpan: Atlas of the Developing Human Brain—Developmental Transcriptome, 2010; https://www.brainspan.org/rnaseq/search/index.html (Accessed 10/31/2022)]