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Epigenome analysis of gliomas with EWSR1-BEND2 fusions

ABSTRACT: Genome-wide DNA methylation profiling of 4 gliomas with EWSR1-BEND fusions with histologic features resembling astroblastoma. The Illumina Infinium EPIC 850k Human DNA Methylation Beadchip was used to obtain DNA methylation profiles across approximately 850,000 CpG sites of genomic DNA extracted from formalin-fixed, paraffin-embedded tumor tissue of 4 gliomas with EWSR1-BEND2 fusions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE183972 | GEO | 2021/11/18

REPOSITORIES: GEO

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Epigenome analysis of gliomas with EWSR1-BEND2 fusions

Project description:Epigenome analysis of gliomas with EWSR1-BEND2 fusions

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Methylation profiling of adult astroblastoma

Project description:Aims and methods: astroblastoma is a rare glial brain tumor with singular morphology. Recurrent MN1-BEND2 fusions have been recently identified in most of pediatric cases. Adolescent and adult cases, however, remain molecularly poorly defined. Here, we performed clinical and molecular characterization of a retrospective cohort of 14 adult and one adolescent gliomas with astroblastic features. Results: strikingly, we found MN1 fusions a rare event in this age group (1/15). Using methylation profiling and targeted sequencing, most cases were reclassified as either pleomorphic xanthoastrocytomas (PXA) or high-grade glioma (HGG). PXA-like ABM show BRAF mutation (6/7 with V600E mutation and 1/7 with G466E mutation) and CD34 expression. Conversely, HGG-like ABM harbored specific mutations of diffuse midline glioma (2/5) or glioblastoma (3/5). These latter patients showed an unfavorable clinical course with significantly shorter overall survival (p = 0.027). MAPK pathway alterations (including FGFR fusion, BRAF and NF1 mutations) were present in 10 of 15 patients and overrepresented in the HGG group (3/5) compared to previously reported prevalence of these alterations in GBM and diffuse midline glioma. Conclusion: We suggest that astroblastoma comprises a variety of molecularly sharply defined entities. Adults’ astroblastomas harboring molecular features of PXA and HGG should be reclassified. CNS high-grade neuroepithelial tumors with MN1 alterations appears to be a truly pediatric entity and is uncommon in adult cases with a histology of astroblastoma. Astroblastic morphology in adults should thus prompt thorough molecular investigation aiming at a clear histomolecular diagnosis and identifying actionable drug targets, especially in MAPK pathway.

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Project description:To characterize BEND2-binding sites on the genome, we conducted ChIP-seq analyses by using testicular lysates from FLAG-BEND2 KI mice. We found BEND2 preferentially binds to simple sequence repeats.

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Identification and characterization of BEND2 as a novel and key regulator of meiosis during mouse spermatogenesis [Histone_CUTRUN]

Project description:To describe the changes of histone modifications in Bend2 knockout mice, we conducted CUT&RUN analyses by using zygotene spermatocytes from Bend2 WT and KO mice with H3K4me3 and H3K27me3 antibodies. We found the enrichment of these histone modifications in the proximal promoter of Bend2 down-regulated genes were disrupted in Bend2 KO mice.

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EWSR1-BEND2 fusion defines an epigenetically distinct subtype of astroblastoma.

Project description: Not available

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Astroblastomas exhibit radial glia stem cell lineages and differential expression of imprinted and X-inactivation escape genes [methylation]

Project description:Astroblastoma (AB) is an unusual brain tumor of unknown origin. We performed an integrated clinicogenomic analysis of 36 AB-like tumors. Lesions with MN1-BEND2 fusions demonstrated decreased promoter methylation and increased expression of IGF2-H19 and DLK1-DIO3 imprinted region genes. They also relatively overexpressed genes highly expressed during fetal brain development prior to 25 post-conception weeks (pcw), including genes enriched in ventricular zone radial glia (vRG), and generally presented in young children. Other tumors highly expressed MAP kinase pathway, PI3K pathway and X-inactivation escape genes. These and a third group of tumors tended to occur in young adults and showed enriched expression of outer radial glia (oRG) and truncated radial glia (tRG) genes, and genes highly expressed after 25 pcw. Many of the latter are involved in axonal migration or synaptic plasticity and are implicated in autism, schizophrenia and other cognitive disorders. Findings suggest that AB-like tumors arise in the context of epigenetic and genetic changes in neural progenitors during fetal and later brain development: early ependymal tumors with MN1-BEND2 fusions (EET-MN1) from vRG-derived progenitor cells, and MAPK/PI3K and classic astroblastomas from oRG- and tRG-derived progenitors, respectively. Lastly, we found that like EET-MN1, immature ependymal cells express IGF2 and may represent an important source of this growth factor in the fetal lateral ventricular zone neural stem cell niche.

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Astroblastomas exhibit radial glia stem cell lineages and differential expression of imprinted and X-inactivation escape genes [Affymetrix]

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Project description:To describe the changes of chromatin accessibility in Bend2 knockout mice, we conducted ATAC-seq analyses by using zygotene spermatocytes from Bend2 WT and KO mice. We found the chromatin state were opened in the proximal promoter of Bend2 up-regulated genes.

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Identification and characterization of BEND2 as a novel and key regulator of meiosis during mouse spermatogenesis [RNA-seq]

Project description:To describe the changes of transcriptome in Bend2 knockout mice, we conducted RNA-seq analyses by using leptotene and zygotene spermatocytes from Bend2 WT and KO mice. We found BEND2 contributes to shutting down the mitotic program and to activating or enhancing the meiotic and post-meiotic program of spermatogenic cells.

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