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Brain Pathology (Zurich, Switzerland) Sep 2020Advances in our understanding of the biological basis and molecular characteristics of ependymal tumors since the latest iteration of the World Health Organization (WHO)... (Review)
Review
Advances in our understanding of the biological basis and molecular characteristics of ependymal tumors since the latest iteration of the World Health Organization (WHO) classification of CNS tumors (2016) have prompted the cIMPACT-NOW group to recommend a new classification. Separation of ependymal tumors by anatomic site is an important principle of the new classification and was prompted by methylome profiling data to indicate that molecular groups of ependymal tumors in the posterior fossa and supratentorial and spinal compartments are distinct. Common recurrent genetic or epigenetic alterations found in tumors belonging to the main molecular groups have been used to define tumor types at intracranial sites; C11orf95 and YAP1 fusion genes for supratentorial tumors and two types of posterior fossa ependymoma defined by methylation group, PFA and PFB. A recently described type of aggressive spinal ependymoma with MYCN amplification has also been included. Myxopapillary ependymoma and subependymoma have been retained as histopathologically defined tumor types, but the classification has dropped the distinction between classic and anaplastic ependymoma. While the cIMPACT-NOW group considered that data to inform assignment of grade to molecularly defined ependymomas are insufficiently mature, it recommends assigning WHO grade 2 to myxopapillary ependymoma and allows grade 2 or grade 3 to be assigned to ependymomas not defined by molecular status.
Topics: Brain Neoplasms; Central Nervous System Neoplasms; Ependyma; Ependymoma; Glioma; Humans; Supratentorial Neoplasms
PubMed: 32502305
DOI: 10.1111/bpa.12866 -
Acta Neuropathologica Mar 2021Two distinct genetically defined entities of ependymoma arising in the supratentorial compartment are characterized by the presence of either a C11orf95-RELA or a...
Two distinct genetically defined entities of ependymoma arising in the supratentorial compartment are characterized by the presence of either a C11orf95-RELA or a YAP-MAMLD1 fusion, respectively. There is growing evidence that supratentorial ependymomas without these genetic features exist. In this study, we report on 18 pediatric non-RELA/non-YAP supratentorial ependymomas that were systematically characterized by means of their histology, immunophenotype, genetics, and epigenomics. Comprehensive molecular analyses included high-resolution copy number analysis, methylation profiling, analysis of fusion transcripts by Nanostring technology, and RNA sequencing. Based upon histological and immunohistochemical features two main patterns were identified-RELA-like (n = 9) and tanycytic ependymomas (n = 6). In the RELA-like group histologically assigned to WHO grade III and resembling RELA-fused ependymomas, tumors lacked nuclear expression of p65-RelA as a surrogate marker for a pathological activation of the NF-κB pathway. Three tumors showed alternative C11orf95 fusions to MAML2 or NCOA1. A methylation-based brain tumor classifier assigned two RELA-like tumors to the methylation class "EP, RELA-fusion"; the others demonstrated no significant similarity score. Of the tanycytic group, 5/6 tumors were assigned a WHO grade II. No gene fusions were detected. Methylation profiling did not show any association with an established methylation class. We additionally identified two astroblastoma-like tumors that both presented with chromothripsis of chromosome 22 but lacked MN1 breaks according to FISH analysis. They revealed novel fusion events involving genes in chromosome 22. One further tumor with polyploid cytogenetics was interpreted as PFB ependymoma by the brain tumor methylation classifier but had no relation to the posterior fossa. Clinical follow-up was available for 16/18 patients. Patients with tanycytic and astroblastoma-like tumors had no relapse, while 2 patients with RELA-like ependymomas died. Our data indicate that in addition to ependymomas discovered so far, at least two more supratentorial ependymoma types (RELA-like and tanycytic) exist.
Topics: Adaptor Proteins, Signal Transducing; Adolescent; Child; Child, Preschool; Ependymoma; Female; Humans; Infant; Male; Supratentorial Neoplasms; Transcription Factor RelA; Transcription Factors; YAP-Signaling Proteins
PubMed: 33481105
DOI: 10.1007/s00401-020-02260-5 -
Neuro-oncology Jun 2022
Topics: Child; Cohort Studies; Ependymoma; Follow-Up Studies; Humans
PubMed: 35325202
DOI: 10.1093/neuonc/noac060 -
Neuro-oncology Apr 2023The diverse cellular constituents of childhood brain tumor ependymoma, recently revealed by single cell RNA-sequencing, may underly therapeutic resistance. Here we use...
BACKGROUND
The diverse cellular constituents of childhood brain tumor ependymoma, recently revealed by single cell RNA-sequencing, may underly therapeutic resistance. Here we use spatial transcriptomics to further advance our understanding of the tumor microenvironment, mapping cellular subpopulations to the tumor architecture of ependymoma posterior fossa subgroup A (PFA), the commonest and most deadly childhood ependymoma variant.
METHODS
Spatial transcriptomics data from intact PFA sections was deconvoluted to resolve the histological arrangement of neoplastic and non-neoplastic cell types. Key findings were validated using immunohistochemistry, in vitro functional assays and outcome analysis in clinically-annotated PFA bulk transcriptomic data.
RESULTS
PFA are comprised of epithelial and mesenchymal histological zones containing a diversity of cellular states, each zone including co-existing and spatially distinct undifferentiated progenitor-like cells; a quiescent mesenchymal zone population, and a second highly mitotic progenitor population that is restricted to hypercellular epithelial zones and that is more abundant in progressive tumors. We show that myeloid cell interaction is the leading cause of mesenchymal transition in PFA, occurring in zones spatially distinct from hypoxia-induced mesenchymal transition, and these distinct EMT-initiating processes were replicated using in vitro models of PFA.
CONCLUSIONS
These insights demonstrate the utility of spatial transcriptomics to advance our understanding of ependymoma biology, revealing a clearer picture of the cellular constituents of PFA, their interactions and influence on tumor progression.
Topics: Humans; Transcriptome; Infratentorial Neoplasms; Brain Neoplasms; Ependymoma; Epithelial-Mesenchymal Transition; Tumor Microenvironment
PubMed: 36215273
DOI: 10.1093/neuonc/noac219 -
Neuro-oncology Jul 2022
Topics: Brain Neoplasms; Child; Ependymoma; Humans; Prospective Studies; Proton Therapy; Protons
PubMed: 35294554
DOI: 10.1093/neuonc/noac066 -
Brain Pathology (Zurich, Switzerland) Jan 2020Ependymomas are primary central nervous system tumors (CNS), arising within the posterior fossa and supratentorial regions of the brain, and in the spine. Over the last... (Review)
Review
Ependymomas are primary central nervous system tumors (CNS), arising within the posterior fossa and supratentorial regions of the brain, and in the spine. Over the last decade, research has resulted in substantial insights into the molecular characteristics of ependymomas, and significant advances have been made in the establishment of a molecular classification system. Ependymomas both within and between the three CNS regions in which they arise, have been shown to contain distinct genetic, epigenetic and cytogenic aberrations, with at least three molecularly distinct subgroups identified within each region. However, these advances in molecular characterization have yet to be translated into clinical practice, with the standard treatment for ependymoma patients largely unchanged. This review summarizes the advances made in the molecular characterization of intracranial ependymomas, outlines the progress made in establishing preclinical models and proposes strategies for moving toward subgroup-specific preclinical investigations and treatment.
Topics: Brain Neoplasms; Central Nervous System Neoplasms; Ependymoma; Humans; Infratentorial Neoplasms; Spinal Neoplasms; Supratentorial Neoplasms
PubMed: 31433520
DOI: 10.1111/bpa.12781 -
International Journal of Molecular... Oct 2022The ubiquitin proteasome system (UPS) is critically important for cellular homeostasis and affects virtually all key functions in normal and neoplastic cells. Currently,... (Review)
Review
The ubiquitin proteasome system (UPS) is critically important for cellular homeostasis and affects virtually all key functions in normal and neoplastic cells. Currently, a comprehensive review of the role of the UPS in ependymoma (EPN) brain tumors is lacking but may provide valuable new information on cellular networks specific to different EPN subtypes and reveal future therapeutic targets. We have reviewed publicly available EPN gene transcription datasets encoding components of the UPS pathway. Reactome analysis of these data revealed genes and pathways that were able to distinguish different EPN subtypes with high significance. We identified differential transcription of several genes encoding ubiquitin E2 conjugases associated with EPN subtypes. The expression of the E2 conjugase genes , , and was elevated in the ST_EPN_RELA subtype. The UBE2C and UBE2S enzymes are associated with the ubiquitin ligase anaphase promoting complex (APC/c), which regulates the degradation of substrates associated with cell cycle progression, whereas UBE2I is a Sumo-conjugating enzyme. Additionally, elevated in ST_EPN_RELA were genes for the E3 ligase and histone deacetylase and the F-box cullin ring ligase adaptor . Cluster analysis demonstrated several genes encoding E3 ligases and their substrate adaptors as EPN subtype specific genetic markers. The most significant Reactome associated with differentially expressed genes for E3 ligases and their adaptors included antigen presentation, neddylation, sumoylation, and the APC/c complex. Our analysis provides several UPS associated factors that may be attractive markers and future therapeutic targets for the subtype-specific treatment of EPN patients.
Topics: Humans; Ubiquitin; Proteasome Endopeptidase Complex; Cullin Proteins; Genetic Markers; gamma-Glutamyl Hydrolase; Anaphase-Promoting Complex-Cyclosome; Ubiquitin-Protein Ligases; Ependymoma; Brain Neoplasms; Histone Deacetylases; Ubiquitin-Conjugating Enzymes
PubMed: 36293188
DOI: 10.3390/ijms232012330 -
Neuro-oncology Oct 2023Accurate identification of brain tumor molecular subgroups is increasingly important. We aimed to establish the most accurate and reproducible ependymoma subgroup...
BACKGROUND
Accurate identification of brain tumor molecular subgroups is increasingly important. We aimed to establish the most accurate and reproducible ependymoma subgroup biomarker detection techniques, across 147 cases from International Society of Pediatric Oncology (SIOP) Ependymoma II trial participants, enrolled in the pan-European "Biomarkers of Ependymoma in Children and Adolescents (BIOMECA)" study.
METHODS
Across 6 European BIOMECA laboratories, we evaluated epigenetic profiling (DNA methylation array); immunohistochemistry (IHC) for nuclear p65-RELA, H3K27me3, and Tenascin-C; copy number analysis via fluorescent in situ hybridization (FISH) and MLPA (1q, CDKN2A), and MIP and DNA methylation array (genome-wide copy number evaluation); analysis of ZFTA- and YAP1-fusions by RT-PCR and sequencing, Nanostring and break-apart FISH.
RESULTS
DNA Methylation profiling classified 65.3% (n = 96/147) of cases as EPN-PFA and 15% (n = 22/147) as ST-ZFTA fusion-positive. Immunohistochemical loss of H3K27me3 was a reproducible and accurate surrogate marker for EPN-PFA (sensitivity 99%-100% across 3 centers). IHC for p65-RELA, FISH, and RNA-based analyses effectively identified ZFTA- and YAP-fused supratentorial ependymomas. Detection of 1q gain using FISH exhibited only 57% inter-center concordance and low sensitivity and specificity while MIP, MLPA, and DNA methylation-based approaches demonstrated greater accuracy.
CONCLUSIONS
We confirm, in a prospective trial cohort, that H3K27me3 immunohistochemistry is a robust EPN-PFA biomarker. Tenascin-C should be abandoned as a PFA marker. DNA methylation and MIP arrays are effective tools for copy number analysis of 1q gain, 6q, and CDKN2A loss while FISH is inadequate. Fusion detection was successful, but rare novel fusions need more extensive technologies. Finally, we propose test sets to guide future diagnostic approaches.
Topics: Child; Adolescent; Humans; Histones; Tenascin; In Situ Hybridization, Fluorescence; Prospective Studies; Biomarkers; Ependymoma
PubMed: 36916248
DOI: 10.1093/neuonc/noad055 -
Acta Bio-medica : Atenei Parmensis May 2021Ependymomas are glial neoplasms of central nervous system originated from the ependymal lining of the brain ventricles and spinal cord central canal, and rarely...
Ependymomas are glial neoplasms of central nervous system originated from the ependymal lining of the brain ventricles and spinal cord central canal, and rarely exfoliated into cerebrospinal fluid (CSF). In this case we report the cytomorphological and immunocytomorphological features of ependymoma in CSF and intraoperative squash preparations, confirmed by histology. Case report. The patient was a nineteen months old female presented at the University hospital of Heraklion, Crete, in a hemicoma, and was intubated. Computed tomography, scanning and magnetic resonance imaging (MRI), were performed and a mass in the posterior fossa was found. A sample of cerebrospinal fluid (CSF) was sent for cytologic evaluation. A diagnosis of ependymoma was rendered, followed by tumor resection, during which intraoperative squash smears for cytologic interpretation were obtained. Cytological consultation disclosed a grade II ependymoma (WHO grade II), with focally anaplastic features (WHO grade III).
Topics: Ependymoma; Female; Humans; Infant; Magnetic Resonance Imaging; Tomography, X-Ray Computed
PubMed: 33988164
DOI: 10.23750/abm.v92i2.9996 -
Neoplasia (New York, N.Y.) May 2023Pediatric intracranial ependymoma has seen a recent exponential expansion of biological findings, rapidly dividing the diagnosis into several subgroups, each with...
Pediatric intracranial ependymoma has seen a recent exponential expansion of biological findings, rapidly dividing the diagnosis into several subgroups, each with specific molecular and clinical characteristics. While such subdivision may complicate clinical conclusions from historical trials, this knowledge also provides an opportunity for interrogating the major clinical and biological questions preventing near-term translation into effective therapy for children with ependymoma. In this article, we briefly review some of the most critical clinical questions facing both patient management and the construct of future trials in childhood ependymoma, as well as explore some of the current barriers to efficient translation of preclinical discovery to the clinic.
Topics: Child; Humans; Brain Neoplasms; Ependymoma; Prognosis
PubMed: 36944298
DOI: 10.1016/j.neo.2023.100895