-
International Journal of Molecular... Jun 2023H3K27M mutant (mut) diffuse midline glioma (DMG) is a lethal cancer with no effective cure. The glycosphingolipids (GSL) metabolism is altered in these tumors and could...
H3K27M mutant (mut) diffuse midline glioma (DMG) is a lethal cancer with no effective cure. The glycosphingolipids (GSL) metabolism is altered in these tumors and could be exploited to develop new therapies. We tested the effect of the glucosylceramide synthase inhibitors (GSI) miglustat and eliglustat on cell proliferation, alone or in combination with temozolomide or ionizing radiation. Miglustat was included in the therapy protocol of two pediatric patients. The effect of H3.3K27 trimethylation on GSL composition was analyzed in ependymoma. GSI reduced the expression of the ganglioside GD2 in a concentration and time-dependent manner and increased the expression of ceramide, ceramide 1-phosphate, sphingosine, and sphingomyelin but not of sphingosine 1-phosphate. Miglustat significantly increased the efficacy of irradiation. Treatment with miglustat according to dose recommendations for patients with Niemann-Pick disease was well tolerated with manageable toxicities. One patient showed a mixed response. In ependymoma, a high concentration of GD2 was found only in the presence of the loss of H3.3K27 trimethylation. In conclusion, treatment with miglustat and, in general, targeting GSL metabolism may offer a new therapeutic opportunity and can be administered in close proximity to radiation therapy. Alterations in H3K27 could be useful to identify patients with a deregulated GSL metabolism.
Topics: Humans; Child; Ceramides; Glioma; Ependymoma
PubMed: 37373053
DOI: 10.3390/ijms24129905 -
Journal of Neuro-oncology Feb 2023Review of the clinicopathologic and genetic features of early ependymal tumor with MN1-BEND2 fusion (EET MN1-BEND2), classical astroblastomas, and recently described... (Review)
Review
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.
Topics: Child; Female; Humans; Brain Neoplasms; Central Nervous System Neoplasms; Glioma; In Situ Hybridization, Fluorescence; Neoplasms, Neuroepithelial; Prognosis; Supratentorial Neoplasms; Trans-Activators; Tumor Suppressor Proteins
PubMed: 36604386
DOI: 10.1007/s11060-022-04222-1 -
Singapore Medical Journal Jan 2016
Topics: Adult; Biopsy; Cerebral Ventricle Neoplasms; Diagnosis, Differential; Humans; Magnetic Resonance Imaging; Male; Neoplasms, Neuroepithelial; Third Ventricle
PubMed: 26831319
DOI: 10.11622/smedj.2016013 -
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 -
Folia Neuropathologica 2017. (Review)
Review
.
Topics: Brain Neoplasms; Glioma; Humans; Neoplasms, Neuroepithelial
PubMed: 28430287
DOI: 10.5114/fn.2017.66708 -
Journal of Cancer Research and... 2015Astroblastoma is a rare neuroepithelial primary brain tumor of uncertain origin. They form 0.45-2.8% of all the neuroglial tumors. This tumor is usually localized in the... (Review)
Review
Astroblastoma is a rare neuroepithelial primary brain tumor of uncertain origin. They form 0.45-2.8% of all the neuroglial tumors. This tumor is usually localized in the cerebral hemisphere of young adults and children. The authors report a case of low-grade astroblastoma in a 16-year-old male and review the relevant literature. The patient presented with 2 months history of progressive headache with projectile vomiting for last 2 months. He underwent gross total resection of the lesion through right temporo-occipital craniotomy. Since tumor showed no evidence of high-grade lesion, adjuvant radiotherapy was not planned. However, the patient developed recurrence of the tumor after 12 months. Localized three-dimensional conformal radiotherapy was planned. In patients harboring anaplastic astroblastoma, gross-total resection and adjuvant therapy after the initial surgery seems to be the best choice. They can be easily misdiagnosed as they are rarely encountered in clinical practice and share common radiological and histopathologic appearance with other glial neoplasms.
Topics: Adolescent; Brain Neoplasms; Humans; Male; Neoplasm Recurrence, Local; Neoplasms, Neuroepithelial; Occipital Lobe; Radiography; Treatment Outcome
PubMed: 26458709
DOI: 10.4103/0973-1482.140800 -
Frontiers in Immunology 2022The glioma tumor microenvironment (TME) is complex and heterogeneous, and multiple emerging and current technologies are being utilized for an improved comprehension and... (Review)
Review
The glioma tumor microenvironment (TME) is complex and heterogeneous, and multiple emerging and current technologies are being utilized for an improved comprehension and understanding of these tumors. Single cell analysis techniques such as single cell genomic and transcriptomic sequencing analysis are on the rise and play an important role in elucidating the glioma TME. These large datasets will prove useful for patient tumor characterization, including immune configuration that will ultimately influence therapeutic choices and especially immune therapies. In this review we discuss the advantages and drawbacks of these techniques while debating their role in the domain of glioma-infiltrating myeloid cells characterization and function.
Topics: Glioblastoma; Glioma; Humans; Myeloid Cells; Myeloid Progenitor Cells; Tumor Microenvironment
PubMed: 35784281
DOI: 10.3389/fimmu.2022.907605 -
Surgical Neurology International 2016Astroblastoma is a rare neuroepithelial tumor that often originates in the cerebral hemisphere of children and young adults. Diagnosis of this obscure neoplasm can be...
BACKGROUND
Astroblastoma is a rare neuroepithelial tumor that often originates in the cerebral hemisphere of children and young adults. Diagnosis of this obscure neoplasm can be difficult because these tumors are so infrequently encountered and share common radiological and neuropathological features of other glial neoplasms. As such, it should be included in the differential diagnosis of astrocytoma and ependymoma if the clinical and radiographic features suggest it. Standardized treatment of astroblastomas remains under dispute because of the lack of knowledge regarding the tumor and a paucity of studies in the literature.
CASE DESCRIPTION
We present a case of a low-grade astroblastoma diagnosed in a 30-year-old female with seizures, headache, and vision changes. She underwent gross total resection and, without evidence of high-grade features, adjuvant therapy was not planned postoperatively. Post-operative surveillance suggested early recurrence, warranting referral to radiation therapy. Patient ended up expiring despite adjuvant therapy secondary to extensive recurrence and tumor metastasis.
CONCLUSIONS
Astroblastoma must be considered in the differential of supratentorial tumors in children and young adults. Treatment of such, as suggested by most recent literature, includes gross total resection and adjuvant radiotherapy for lesions exhibiting high-grade features.
PubMed: 28144474
DOI: 10.4103/2152-7806.195583 -
Neurobiology of Disease Nov 2023Epilepsy, a common complication of diffuse low-grade gliomas (DLGGs; diffuse oligodendroglioma and astrocytoma collectively), severely compromises the quality of life of...
Epilepsy, a common complication of diffuse low-grade gliomas (DLGGs; diffuse oligodendroglioma and astrocytoma collectively), severely compromises the quality of life of patients. DLGG epileptogenicity may primarily be generated by interactions between the tumor and the neocortex. Neuronal uptake of dysfunctional mitochondria from the extracellular environment can lead to abnormal neuronal discharge. Mitochondrial dysfunction is frequently observed in gliomas that can transmigrate across the plasma membranes. Here, we examined the role of the Rho GTPase-activating protein 44 (RICH2) in mitochondrial dynamics and DLGG-related epilepsy. We investigated the association between mitochondrial and RICH2 expression in human DLGG tissues using immunohistochemistry. We examined the association between RICH2 and epilepsy in nude mouse glioma models by electrophysiology. The effect of RICH2 on mitochondrial morphology and calcium motility were assessed by single cell fluorescence microscopy. Quantitative RT-PCR (qRT-PCR) and Western blot analysis were performed to characterize RICH2 induced expression changes in the genes related to mitochondrial dynamics, mitogenesis and mitochondrial function. We found that RICH2 expression was higher in oligodendroglioma than in astrocytoma and was correlated with better prognosis and higher epilepsy rate in patients. The expression of mitochondria may be associated with clinical DLGG-related epilepsy and reduced by RICH2 overexpression. And RICH2 could promote DLGG-related epilepsy in tumorigenic nude mice. RICH2 overexpression decreased calcium flow and the mitochondria released from glioma cells (SW1088 and U251) into the extracellular environment, potentially via downregulation of MFN-1/MFN-2 levels which suggests reduced mitochondrial fusion. In addition, we observed decreased mitochondrial trafficking into neurons (released from glioma cells and trafficked into neurons), which could explain the higher incidence of DLGG-related epilepsy due to reduced neuroprotection. Furthermore, RICH2 downregulated MAPK/ERK/HIF-1 pathway. In conclusion, these results suggest that RICH2 could promote epilepsy by (i) inhibiting mitochondrial fusion via MFN downregulation and Drp-1 upregulation; (ii) altering the MAPK/ERK/Hif-1 signaling axis. RICH2 may be a potential target in the treatment of DLGG-related epilepsy.
Topics: Animals; Mice; Humans; Oligodendroglioma; Calcium; Mice, Nude; Quality of Life; Glioma; Mitochondria; Astrocytoma
PubMed: 37926169
DOI: 10.1016/j.nbd.2023.106344 -
British Medical Journal Sep 1968
Topics: Child; Female; Humans; Male; Neuroblastoma; Sex Factors
PubMed: 5673954
DOI: No ID Found