RESUMO
Central nervous system (CNS) tumors are the leading cause of pediatric cancer death, and these patients have an increased risk for developing secondary neoplasms. Due to the low prevalence of pediatric CNS tumors, major advances in targeted therapies have been lagging compared to other adult tumors. We collect single nuclei RNA-seq data from 84,700 nuclei of 35 pediatric CNS tumors and three non-tumoral pediatric brain tissues and characterize tumor heterogeneity and transcriptomic alterations. We distinguish cell subpopulations associated with specific tumor types including radial glial cells in ependymomas and oligodendrocyte precursor cells in astrocytomas. In tumors, we observe pathways important in neural stem cell-like populations, a cell type previously associated with therapy resistance. Lastly, we identify transcriptomic alterations among pediatric CNS tumor types compared to non-tumor tissues, while accounting for cell type effects on gene expression. Our results suggest potential tumor type and cell type-specific targets for pediatric CNS tumor treatment. Here we address current gaps in understanding single nuclei gene expression profiles of previously under-investigated tumor types and enhance current knowledge of gene expression profiles of single cells of various pediatric CNS tumors.
Assuntos
Neoplasias do Sistema Nervoso Central , Ependimoma , Regulação Neoplásica da Expressão Gênica , Transcriptoma , Humanos , Criança , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/metabolismo , Ependimoma/genética , Ependimoma/patologia , Ependimoma/metabolismo , Pré-Escolar , Astrocitoma/genética , Astrocitoma/patologia , Astrocitoma/metabolismo , Perfilação da Expressão Gênica/métodos , Feminino , RNA-Seq , Masculino , Adolescente , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Núcleo Celular/metabolismo , Núcleo Celular/genéticaRESUMO
BACKGROUND: Ependymomas (EPNs) of the spinal region are a heterogeneous group of tumors that account for 17.6 % in adults. Four types have been recognized: subependymoma, spinal ependymoma (Sp-EPN), myxopapillary ependymoma (MPE), and Sp-EPN-MYCN amplified, each with distinct histopathological and molecular features. METHODS: This study investigated the clinical and pathological characteristics and MYCN expression levels of 35 Sp-EPN and MPE cases diagnosed at a tertiary university hospital over a decade-long period. RESULTS: Twenty-five cases were Sp-EPN and 10 cases were MPE, and were graded as WHO grade 2, except for 1 Sp-EPN case with grade 3 features. The most common symptoms were lower back pain and difficulty in walking. Radiology showed different tumor sizes and locations along the spinal cord, with MPEs exclusively in the lumbosacral region. Surgery was the main treatment, and gross total resection was achieved in all cases except for one. Immunohistochemistry showed low Ki-67 proliferation indices in all cases, and no MYCN expression. During follow-up, 3 (8.6 %) cases recurred and/or metastasized and 5 cases (14.3 %) died. No significant difference was found in disease-free survival or overall survival between Sp-EPN and MPE cases. However, 3 cases with grade 2 histology demonstrated recurrence and/or metastasis, despite the lack of MYCN expression. CONCLUSION: Our results underscore the multifactorial nature of tumor aggressiveness in EPNs of the spinal region. This study enhances our knowledge of the clinical and pathological features of Sp-EPNs and MPEs and highlights the need for better diagnostic and prognostic markers in these rare tumors.
Assuntos
Ependimoma , Proteína Proto-Oncogênica N-Myc , Neoplasias da Medula Espinal , Humanos , Ependimoma/patologia , Ependimoma/genética , Ependimoma/metabolismo , Ependimoma/diagnóstico , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Proteína Proto-Oncogênica N-Myc/genética , Proteína Proto-Oncogênica N-Myc/metabolismo , Neoplasias da Medula Espinal/patologia , Neoplasias da Medula Espinal/metabolismo , Neoplasias da Medula Espinal/genética , Neoplasias da Medula Espinal/diagnóstico , Adulto Jovem , Idoso , Adolescente , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/análise , Imuno-Histoquímica/métodosRESUMO
Members of the HDAC family are predictive biomarkers and regulate the tumorigenesis in several cancers. However, the role of these genes in the biology of intracranial ependymomas (EPNs) remains unexplored. Here, an analysis of eighteen HDACs genes in an EPN transcriptomic dataset, revealed significantly higher levels of HDAC4 in supratentorial ZFTA fusion (ST-ZFTA) compared with ST-YAP1 fusion and posterior fossa EPNs, while HDAC7 and SIRT2 were downregulated in ST-ZFTA. HDAC4 was also overexpressed in ST-ZFTA as measured by single-cell RNA-Seq, quantitative real time-polymerase chain reaction, and immunohistochemistry. Survival analyses showed a significantly worse outcome for EPNs with higher HDAC4 and SIRT1 mRNA levels. Ontology enrichment analysis showed an HDAC4-high signature consistent with viral processes while collagen-containing extracellular matrix and cell-cell junction were enriched in those with an HDAC4-low signature. Immune gene analysis demonstrated a correlation between HDAC4 expression and low levels of NK resting cells. Several small molecules compounds targeting HDAC4 and ABCG2, were predicted by in silico analysis to be effective against HDAC4-high ZFTA. Our results provide novel insights into the biology of the HDAC family in intracranial ependymomas and reveal HDAC4 as a prognostic marker and potential therapeutic target in ST-ZFTA.
Assuntos
Neoplasias Encefálicas , Ependimoma , Humanos , Prognóstico , Fatores de Transcrição/genética , Ependimoma/genética , Ependimoma/metabolismo , Neoplasias Encefálicas/genética , Perfilação da Expressão Gênica , Histona Desacetilases/genética , Proteínas Repressoras/genéticaRESUMO
The spatiotemporal regulation of cell fate specification in the human developing spinal cord remains largely unknown. In this study, by performing integrated analysis of single-cell and spatial multi-omics data, we used 16 prenatal human samples to create a comprehensive developmental cell atlas of the spinal cord during post-conceptional weeks 5-12. This revealed how the cell fate commitment of neural progenitor cells and their spatial positioning are spatiotemporally regulated by specific gene sets. We identified unique events in human spinal cord development relative to rodents, including earlier quiescence of active neural stem cells, differential regulation of cell differentiation and distinct spatiotemporal genetic regulation of cell fate choices. In addition, by integrating our atlas with pediatric ependymomas data, we identified specific molecular signatures and lineage-specific genes of cancer stem cells during progression. Thus, we delineate spatiotemporal genetic regulation of human spinal cord development and leverage these data to gain disease insight.
Assuntos
Ependimoma , Células-Tronco Neurais , Criança , Feminino , Gravidez , Humanos , Medula Espinal , Ependimoma/genética , Ependimoma/metabolismo , Diferenciação Celular/genética , Células-Tronco Neurais/fisiologia , Expressão Gênica , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento/genéticaRESUMO
Tumors of the Central Nervous System (CNS) represent the leading cause of cancer-related deaths in children. Current treatment options are not curative for most malignant histologies, and intense preclinical and clinical research is needed to develop more effective therapeutic interventions against these tumors, most of which meet the FDA definition for orphan diseases. Increased attention is being paid to the repositioning of already-approved drugs for new anticancer indications as a fast-tracking strategy for identifying new and more effective therapies. Two pediatric CNS tumors, posterior fossa ependymoma (EPN-PF) type A and diffuse midline glioma (DMG) H3K27-altered, share loss of H3K27 trimethylation as a common epigenetic hallmark and display early onset and poor prognosis. These features suggest a potentially common druggable vulnerability. Successful treatment of these CNS tumors raises several challenges due to the location of tumors, chemoresistance, drug blood-brain barrier penetration, and the likelihood of adverse side effects. Recently, increasing evidence demonstrates intense interactions between tumor cell subpopulations and supportive tumor microenvironments (TMEs) including nerve, metabolic, and inflammatory TMEs. These findings suggest the use of drugs, and/or multi-drug combinations, that attack both tumor cells and the TME simultaneously. In this work, we present an overview of the existing evidence concerning the most preclinically validated noncancer drugs with antineoplastic activity. These drugs belong to four pharmacotherapeutic classes: antiparasitic, neuroactive, metabolic, and anti-inflammatory. Preclinical evidence and undergoing clinical trials in patients with brain tumors, with special emphasis on pediatric EPN-PF and DMG, are summarized and critically discussed.
Assuntos
Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Ependimoma , Humanos , Criança , Reposicionamento de Medicamentos , Ependimoma/tratamento farmacológico , Ependimoma/genética , Ependimoma/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/metabolismo , Neoplasias do Sistema Nervoso Central/metabolismo , Barreira Hematoencefálica/metabolismo , Microambiente TumoralRESUMO
Nuclear localization of HIPPO-YAP fusion proteins has been implicated in supratentorial ependymoma development. Here, unexpectedly, we find that liquid-liquid phase separation, rather than nuclear localization, of recurrent patient-derived YAP fusions, YAP-MAMLD1 and C11ORF95-YAP, underlies ependymoma tumourigenesis from neural progenitor cells. Mutagenesis and chimaera assays demonstrate that an intrinsically disordered region promotes oligomerization of the YAP fusions into nuclear, puncta-like, membrane-less condensates. Oligomerization and nuclear condensates induced by YAP fusion with a coiled-coil domain of transcriptional activator GCN4 also promote ependymoma formation. YAP-MAMLD1 concentrates transcription factors and co-activators, including BRD4, MED1 and TEAD, in condensates while excluding transcriptional repressive PRC2, and induces long-range enhancer-promoter interactions that promote transcription and oncogenic programmes. Blocking condensate-mediated transcriptional co-activator activity inhibits tumourigenesis, indicating a critical role of liquid phase separation for YAP fusion oncogenic activity in ependymoma. YAP fusions containing the intrinsically disordered region features are common in human tumours, suggesting that nuclear condensates could be targeted to treat YAP-fusion-induced cancers.
Assuntos
Ependimoma , Fatores de Transcrição , Humanos , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Carcinogênese/genética , Proteínas de Ciclo Celular/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Ependimoma/genética , Ependimoma/metabolismo , Ependimoma/patologia , Proteínas Nucleares/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Proteínas de Sinalização YAP , Núcleo Celular/metabolismo , Transcrição GênicaRESUMO
BACKGROUND: Supratentorial ependymomas (STEs) are an aggressive group of ependymomas, topographically distinct from their posterior fossa and spinal counterparts. Zinc finger translocation associated (ZFTA) fusion-positive cases have been reported to account for the majority of STEs, although data on its association with poorer outcomes are inconsistent. MATERIALS AND METHODS: We assessed the prevalence of the ZFTA fusion by reverse-transcription polymerase chain reaction and fluorescence in situ hybridization in a cohort of 61 patients (68 samples) with STE. Our primary outcome was to determine the role of the ZFTA fusion on progression-free and overall survival of patients with STE. Our secondary objectives were to assess the impact of ZFTA fusion on nuclear factor (NF)-kB pathway signaling via surrogate markers of this pathway, namely COX-2, CCND1, and L1 cell adhesion molecule. RESULTS: ZFTA fusion was noted in 21.3% of STEs in our cohort. The presence of this rearrangement did not significantly impact the progression-free or overall survival of patients with STEs and was not associated with upregulation of markers of the NF-kB pathway. Only gross total resection was significantly associated with better progression-free survival. CONCLUSIONS: In contradiction to previous reports from across the world, the ZFTA fusion is far less prevalent among our population. It does not appear to drive NF-kB signaling or significantly affect outcomes. Gross total resection must be attempted in all cases of STE and adjuvant radiation and/or chemotherapy employed when gross total resection is not achieved.
Assuntos
Ependimoma , Neoplasias Supratentoriais , Ependimoma/genética , Ependimoma/metabolismo , Ependimoma/cirurgia , Humanos , Hibridização in Situ Fluorescente , NF-kappa B/metabolismo , Prevalência , Neoplasias Supratentoriais/genética , Neoplasias Supratentoriais/metabolismo , Neoplasias Supratentoriais/cirurgia , Fator de Transcrição RelA/genética , Fator de Transcrição RelA/metabolismo , Translocação Genética/genética , Dedos de ZincoRESUMO
OBJECTIVE: Ependymomas are biologically diverse tumors with five major genomic subgroups. However, intratumor heterogeneity continues to be poorly understood. The present study characterized the metabolic landscapes of ependymoma subgroups at the single-cell level. METHODS: Expression profiles from 11,200 ependymoma single cells derived from the five major subgroups and 7,200 ependymoma-derived non-neoplastic cells were computationally analyzed using a robust workflow to elucidate relative differences in metabolic pathway activities. RESULTS: Dimensionality reduction using metabolic expression profiles exhibited clustering corresponding to each tumor subgroup, but non-neoplastic cells exhibited no discernable differences between subgroups. From the 80 metabolic pathways examined, over 75 pathways had significantly different activity scores between ependymoma subgroups. Further analysis of metabolic heterogeneity suggests that mitochondrial oxidative phosphorylation accounts for considerable metabolic variation within tumor subgroups and non-neoplastic cells of the same cell type. Drug metabolism pathways, specifically those involving cytochromes P450, were also found to be major contributors to heterogeneity. CONCLUSIONS: Ependymoma subgroups display distinct metabolic differences as evaluated through gene expression profiles with certain pathways contributing greatly to intra-subgroup variation. These results may account for variation in tumor metabolism, treatment response, and potential targeting approaches that disrupt metabolic signalling.
Assuntos
Ependimoma/genética , Ependimoma/metabolismo , Redes e Vias Metabólicas , Metaboloma , Transcriptoma , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Análise de Sequência de RNA , Análise de Célula ÚnicaRESUMO
Nuclear factor-kappa B (NF-κB) signaling is an intracellular signaling pathway involved in inflammatory responses and the pathogenesis of various cancers, including ependymoma, which is a rare and chemotherapy-resistant glioma. Several isoforms of fusion proteins that consist of a nuclear protein, zinc finger translocation associated (ZFTA), and RELA (ZFTA-RELA), an NF-κB-signaling effector transcription factor, cause excessive activation of the NF-κB signaling pathway and result in supratentorial ependymomas (ST-EPN-RELA). As inhibitors of NF-κB activity induced by ZFTA-RELA are expected to be therapeutic agents for ST-EPN-RELA, we established an NF-κB responsive luciferase reporter cell line that expresses the most common isoform of ZFTA-RELA in a doxycycline-dependent manner. Using this reporter cell line, we screened fungus extracts for compounds that inhibit the NF-κB activity induced by ZFTA-RELA expression and identified aszonalenin, an alkaloid from Aspergillus novofumigatus. We also purified analogs of aszonalenin, namely acetylaszonalenin and epi-aszonalenin B and C. In a luciferase assay using cells constitutively expressing luciferase (counter assay), acetylaszonalenin and epi-aszonalenin C showed non-specific inhibition of the luciferase activity. Aszonalenin and epi-aszonalenin B inhibited the NF-κB responsive luciferase activity by expressing ZFTA-RELA more strongly than the luciferase activity in the counter assay. The upregulation of endogenous NF-κB responsive genes, such as CCND1, ICAM1, and L1CAM, by ZFTA-RELA expression was inhibited by epi-aszonalenin B, but not by aszonalenin. This study suggests that epi-aszonalenin B may be a lead compound for the therapeutic development of ST-EPN-RELA.
Assuntos
Aspergillus/química , Ependimoma/genética , Alcaloides Indólicos/farmacologia , NF-kappa B/antagonistas & inibidores , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Fator de Transcrição RelA/genética , Western Blotting , Ciclina D1/genética , Ciclina D1/metabolismo , Doxiciclina/farmacologia , Ependimoma/metabolismo , Ependimoma/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Células HeLa , Humanos , Alcaloides Indólicos/química , Molécula 1 de Adesão Intercelular , Estrutura Molecular , NF-kappa B/metabolismo , Molécula L1 de Adesão de Célula Nervosa/genética , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Proteínas Nucleares/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição RelA/metabolismoRESUMO
Ependymomas are rare central nervous system tumours that can arise in the brain's supratentorial region or posterior fossa, or in the spinal cord. In 1924, Percival Bailey published the first comprehensive study of ependymomas. Since then, and especially over the past 10 years, our understanding of ependymomas has grown exponentially. In this Review, we discuss the evolution in knowledge regarding ependymoma subgroups and the resultant clinical implications. We also discuss key oncogenic and tumour suppressor signalling pathways that regulate tumour growth, the role of epigenetic dysregulation in the biology of ependymomas, and the various biological features of ependymoma tumorigenesis, including cell immortalization, stem cell-like properties, the tumour microenvironment and metastasis. We further review the limitations of current therapies such as relapse, radiation-induced cognitive deficits and chemotherapy resistance. Finally, we highlight next-generation therapies that are actively being explored, including tyrosine kinase inhibitors, telomerase inhibitors, anti-angiogenesis agents and immunotherapy.
Assuntos
Ependimoma , Recidiva Local de Neoplasia , Biologia , Ependimoma/genética , Ependimoma/metabolismo , Ependimoma/terapia , Humanos , Oncogenes , Microambiente TumoralRESUMO
AIMS: An ependymoma shows divergent morphological and molecular features depending on their location. The paired box 6 (PAX6) transcription factor is a putative tumour suppressor and drives cancer cells towards a stem cell-like state. A transcriptome study reported high PAX6 expression in ependymal tumours, but data on protein expression are lacking. METHODS: We, therefore, analysed PAX6 expression by immunohistochemistry in 172 ependymoma samples and correlated its expression to histology, WHO grade, anatomical location and molecular subgroups. RESULTS: Mean PAX6 nuclear expression in ependymoma was 27.5% (95% CI 23.3 to 31.7). PAX6 expression in subependymoma (mean: 5%) was significantly lower compared with myxopapillary (30%), WHO grade II (26%) and anaplastic ependymoma (35%). Supratentorial ependymomas also displayed significant lower PAX6 levels (15%) compared with spinal cord tumours (30%). Expression levels in YAP1-fused ependymoma (41%) were higher compared with REL-associated protein (RELA)-fusion positive tumours (17%), while PAX6 expression was similar in posterior fossa group A (33%) and B (29%) ependymomas. Kaplan-Meier analysis in RELA-fusion positive ependymomas and posterior fossa group B showed a significant better outcome for PAX6 at or above the cut-off of 19.45% compared with tumours with PAX6 below the cut-off. CONCLUSIONS: We demonstrate that PAX6 is frequently expressed in human ependymal tumours and immunohistochemistry may be helpful in determining prognostic relevant subgroups.
Assuntos
Neoplasias Encefálicas , Ependimoma , Humanos , Prognóstico , Ependimoma/genética , Ependimoma/metabolismo , Ependimoma/patologia , Imuno-Histoquímica , Fatores de Transcrição , Fator de Transcrição PAX6/genéticaRESUMO
The cIMPACT-NOW Update 7 has replaced the WHO nosology of "ependymoma, RELA fusion positive" by "Supratentorial-ependymoma, C11orf95-fusion positive". This modification reinforces the idea that supratentorial-ependymomas exhibiting fusion that implicates the C11orf95 (now called ZFTA) gene with or without the RELA gene, represent the same histomolecular entity. A hot off the press molecular study has identified distinct clusters of the DNA methylation class of ZFTA fusion-positive tumors. Interestingly, clusters 2 and 4 comprised tumors of different morphologies, with various ZFTA fusions without involvement of RELA. In this paper, we present a detailed series of thirteen cases of non-RELA ZFTA-fused supratentorial tumors with extensive clinical, radiological, histopathological, immunohistochemical, genetic and epigenetic (DNA methylation profiling) characterization. Contrary to the age of onset and MRI aspects similar to RELA fusion-positive EPN, we noted significant histopathological heterogeneity (pleomorphic xanthoastrocytoma-like, astroblastoma-like, ependymoma-like, and even sarcoma-like patterns) in this cohort. Immunophenotypically, these NFκB immunonegative tumors expressed GFAP variably, but EMA constantly and L1CAM frequently. Different gene partners were fused with ZFTA: NCOA1/2, MAML2 and for the first time MN1. These tumors had epigenetic homologies within the DNA methylation class of ependymomas-RELA and were classified as satellite clusters 2 and 4. Cluster 2 (n = 9) corresponded to tumors with classic ependymal histological features (n = 4) but also had astroblastic features (n = 5). Various types of ZFTA fusions were associated with cluster 2, but as in the original report, ZFTA:MAML2 fusion was frequent. Cluster 4 was enriched with sarcoma-like tumors. Moreover, we reported a novel anatomy of three ZFTA:NCOA1/2 fusions with only 1 ZFTA zinc finger domain in the putative fusion protein, whereas all previously reported non-RELA ZFTA fusions have 4 ZFTA zinc fingers. All three cases presented a sarcoma-like morphology. This genotype/phenotype association requires further studies for confirmation. Our series is the first to extensively characterize this new subset of supratentorial ZFTA-fused ependymomas and highlights the usefulness of ZFTA FISH analysis to confirm the existence of a rearrangement without RELA abnormality.
Assuntos
Ependimoma/genética , Proteínas/genética , Neoplasias Supratentoriais/genética , Adolescente , Adulto , Criança , Pré-Escolar , Metilação de DNA/genética , Ependimoma/classificação , Ependimoma/metabolismo , Ependimoma/patologia , Feminino , Fusão Gênica/genética , Genótipo , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Lactente , Masculino , NF-kappa B/metabolismo , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Coativador 1 de Receptor Nuclear/genética , Coativador 2 de Receptor Nuclear/genética , Fenótipo , Neoplasias Supratentoriais/classificação , Neoplasias Supratentoriais/metabolismo , Neoplasias Supratentoriais/patologia , Transativadores/genética , Fator de Transcrição RelA/genética , Proteínas Supressoras de Tumor/genética , Adulto JovemRESUMO
Childhood ependymomas are heterogenous chemoresistant neoplasms arising from aberrant stem-like cells. Epigenome deregulation plays a pivotal role in ependymoma pathogenesis, suggesting that epigenetic modifiers hold therapeutic promise against this disease. Bromodomain and extraterminal domain (BET) proteins are epigenome readers of acetylated signals in histones and coactivators for oncogenic and stemness-related transcriptional networks, including MYC/MYCN (Proto-Oncogene, BHLH Transcritpion Factor)-regulated genes. We explored BET inhibition as an anticancer strategy in a panel of pediatric patient-derived ependymoma stem cell models by OTX015-mediated suppression of BET/acetylated histone binding. We found that ependymoma tissues and lines express BET proteins and their targets MYC and MYCN. In vitro, OTX015 reduced cell proliferation by inducing G0/G1-phase accumulation and apoptosis at clinically tolerable doses. Mechanistically, inhibitory p21 and p27 increased in a p53-independent manner, whereas the proliferative driver, phospho-signal transducer and activator of transcription 3 (STAT3), decreased. Upregulation of apoptosis-related proteins and survivin downregulation were correlated with cell line drug sensitivity. Minor alterations of MYC/MYCN expression were reported. In vivo, OTX015 significantly improved survival in 2/3 orthotopic ependymoma models. BET proteins represent promising targets for pharmaceutical intervention with OTX015 against ependymoma. The identification of predictive determinants of sensitivity may help identify ependymoma molecular subsets more likely to benefit from BET inhibitor therapies.
Assuntos
Acetanilidas/farmacologia , Antineoplásicos/farmacologia , Ciclo Celular/efeitos dos fármacos , Ependimoma/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/farmacologia , Proteína Proto-Oncogênica N-Myc/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-myc/antagonistas & inibidores , Animais , Linhagem Celular Tumoral , Ependimoma/metabolismo , Ependimoma/patologia , Humanos , Masculino , Camundongos , Camundongos Nus , Proteína Proto-Oncogênica N-Myc/metabolismo , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas c-myc/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The P53N gene maps precisely to human chromosome sub-band 22q12.1-12.3, a region where loss of heterozygosity has been reported in 30% of astrocytic tumors and associated with progression to anaplasia. Moreover, a putative tumor suppressor gene has been indicated on 22q11 region involved in pathogenesis of ependymal tumors. Our objectives to examine the expression level of novel membrane-associated protein (termed P53N) encoded by a novel human gene on chromosome 22q12.1-12.3 in glioblastomas and ependymomas. Serial analysis of gene expression (SAGE) and immunofluorescence analysis of the P53N in the brain tumor tissues were performed. Our analysis revealed that there was high expression of the P53N mRNA in brain ependymoma and brain well-differentiated astrocytoma libraries. The P53N protein. P53N protein contains a high mobility group (HMG) domain at amino acid positions 301 to 360 expressed highly in glioblastoma and ependymoma specimens. Anti-P53N carboxyl-terminal peptide antibody localized the P53N protein to the cytoplasmic membranes of protoplasmic astrocytes in the glioblastoma and ependymoma specimens. These results are in good agreement with the SAGE analysis and the predicted transmembrane topology for the P53N protein and support a possible transmembrane model in which the P53N contains a predicted transmembrane region with its amino terminus localized to the inside of the cytoplasmic membrane.
Assuntos
Neoplasias Encefálicas/metabolismo , Cromossomos Humanos Par 22/genética , Ependimoma/metabolismo , Glioblastoma/metabolismo , Proteínas de Grupo de Alta Mobilidade/genética , Neoplasias Encefálicas/genética , Clonagem Molecular , Ependimoma/genética , Glioblastoma/genética , Proteínas de Grupo de Alta Mobilidade/química , Proteínas de Grupo de Alta Mobilidade/metabolismo , Humanos , Domínios ProteicosRESUMO
The objectives of this study were to explore the possible mechanisms of pediatric ependymoma using bioinformatics methods and provide potential genes and signaling pathways for pediatric ependymoma study. The data of GES74195 from Gene Expression Ominibus was analyzed by R language for pediatric ependymoma study. The differentially expressed genes were explored using gene set enrichment analysis, search tool for the retrieval of interacting genes, Cytoscape as well as other mainstream bioinformatics methods. Extracellular matrix-receptors interaction pathways and focal adhesion pathway were demonstrated as the key signaling pathway for pediatric ependymoma. The potential hub genes enriched in the two signaling pathways were regarded as final hub genes for this microarray analysis. The development and progression of pediatric ependymoma were associated with epithelial-mesenchymal-transition. Various potential hub genes and potential key signaling pathways in order to further explore their values in the diagnosis and treatment of this disease in the future.
Assuntos
Neoplasias Encefálicas/genética , Ependimoma/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Criança , Biologia Computacional , Ependimoma/metabolismo , Ependimoma/patologia , Transição Epitelial-Mesenquimal/genética , Ontologia Genética , Humanos , Análise em Microsséries , Estudos Retrospectivos , Transdução de Sinais , Neoplasias da Medula Espinal/genética , Neoplasias da Medula Espinal/metabolismo , Neoplasias da Medula Espinal/patologia , TranscriptomaRESUMO
PURPOSE: Supratentorial extraventricular ependymoma (SEE) is a rare subset of ependymomas located in the supratentorial parenchyma, and little is known regarding its management and prognosis. Our study aimed to reveal the prognostic factors in patients with SEE and the roles of programmed death ligand-1 (PD-L1), programmed cell death protein 1 (PD-1), Ki-67, and neural cell adhesion molecule L1 (L1CAM) in predicting these patients' outcomes. METHODS: We retrospectively studied the clinical features and prognostic factors in 48 patients with SEE admitted to our center from April 2008 to October 2018. Tissue slides were constructed from patient samples, and PD-L1, PD-1, Ki-67, and L1CAM expression levels were evaluated by immunohistochemistry. RESULTS: Patients with gross total resection (GTR) had better progression-free survival than patients with subtotal resection (STR). Moreover, the recurrence hazard ratios in patients with STR at 3, 5, and 10 years were 8.746, 6.866 and 3.962 times those of patients with GTR, respectively. PD-L1 positivity predicted worse progression-free survival, while the recurrence hazard ratios for patients with PD-L1 positivity at 3, 5, and 10 years were 10.445, 5.539, and 3.949 times those of patients with PD-L1 negativity, respectively. Multivariate analysis revealed that PD-L1 expression and GTR could independently predict outcomes in patients with SEE. CONCLUSION: PD-L1 expression was an independent and more readily obtained predictor of outcomes, representing a simple and reliable biological prognostic factor for patients with SEE. Further studies are needed to explore PD-L1 inhibitor treatment for patients with ependymoma. CLINICAL TRIAL REGISTRATION: No clinical trials were performed in the study.
Assuntos
Antígeno B7-H1/metabolismo , Ependimoma/patologia , Recidiva Local de Neoplasia/patologia , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Supratentoriais/patologia , Adolescente , Adulto , Criança , Pré-Escolar , Ependimoma/imunologia , Ependimoma/metabolismo , Ependimoma/cirurgia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/cirurgia , Prognóstico , Estudos Retrospectivos , Neoplasias Supratentoriais/imunologia , Neoplasias Supratentoriais/metabolismo , Neoplasias Supratentoriais/cirurgia , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND AND PURPOSE: There are important differences in the treatment and prognosis of adult intracranial low-grade ependymomas (grade II) versus anaplastic ependymomas (grade III). We evaluated the value of the apparent diffusion coefficient (ADC) for differentiating these two tumors and further investigated the relationship between ADC values and the Ki-67 proliferation index. METHODS: Clinical and preoperative magnetic resonance imaging data of 35 cases of adult intracranial ependymomas were retrospectively analyzed, including 20 low-grade ependymomas and 15 anaplastic ependymomas. The minimum ADC (ADCmin), average ADC (ADCmean), and normalized ADC (nADC) were compared between the two groups. Receiver operating characteristic curves were drawn to evaluate the differentiating accuracy of ADC values. The Ki-67 proliferation index of the solid tumor components was also measured to explore its relationship with ADC values. RESULTS: The ADCmin (.89 ± .17 vs. .66 ± .09 × 10-3 mm2 /second), ADCmean (.98 ± .21 vs. .72 ± .11 × 10-3 mm2 /second), and nADC (1.38 ± .31 vs. 1.02 ± .18 × 10-3 mm2 /second) were significantly higher in adult intracranial low-grade ependymomas than anaplastic ependymomas cases (all P < .05). ADCmean best distinguished the two groups, with an area under the curve value of .900. Using .716 × 10-3 mm2 /second as the optimal threshold, the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the two groups were 66.7%, 100%, 85.7%, 100%, and 80%, respectively. ADCmin (r = -.490), ADCmean (r = -.449), and nADC (r = -.425) showed significant negative correlations with the Ki-67 proliferation index (all P < .05). CONCLUSIONS: ADC values can differentiate adult intracranial low-grade ependymomas and anaplastic ependymomas, which could improve the preoperative diagnostic accuracy of these two tumors and guide their treatment.
Assuntos
Ependimoma/diagnóstico por imagem , Ependimoma/metabolismo , Antígeno Ki-67/metabolismo , Imageamento por Ressonância Magnética , Adulto , Idoso , Proliferação de Células , Diagnóstico Diferencial , Difusão , Ependimoma/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Estudos RetrospectivosRESUMO
BACKGROUND: 5-aminolevulinic acid (5-ALA) use is well established in the resection of adult high-grade gliomas. There is growing interest in its usefulness in the paediatric population. The potential benefit of 5-ALA-guided resection motivated our unit to offer the established adult protocol as off-label use. OBJECTIVE: to determine if 5-ALA guided resection was routinely useful and offered increased gross total resection (GTR) results. METHODS: Nineteen patients harbouring a posterior fossa tumour suggestive of either an ependymoma or medulloblastoma (MB) underwent surgery between January 2018 and October 2019. The mean age was 5 years (range 2-12 years). A dose of 20 mg/kg of 5-ALA (Gliolan®) was given 4 h preoperatively. Intraoperatively, the tumours were viewed under violet-blue light and the presence of fluorescence was recorded. Fluorescence status was compared with histopathological classification and grade, Ki-67 index, GTR rate, and a subjective determination of "usefulness" was determined. RESULTS: The case series included ependymoma grade II (n = 6), ependymoma grade III (n = 4), and MB grade IV (n = 9). For the combined cohort, the strong fluorescence rate was 68% (n = 13), the heterogenous fluorescence rate was 26% (n = 5), and the completely negative fluorescence rate was 5% (n = 1). The strong fluorescence rate of 90% found in the combined ependymoma group compared to the 45% strong fluorescence rate in the MB group was statistically significant (p = 0.05). Within the MB group the Ki-67 index was found to be significantly higher in the strongly fluorescent group as opposed to the patchy or non-fluorescent group (77.5 vs. 40%, p = 0.016). Fluorescence was determined to be useful in 63% of all cases. There was no significant relationship between fluorescence and GTR. The relationship between perceived usefulness and resection was not statistically significant. No adverse drug reactions were recorded. CONCLUSION: This case series adds to the growing body of evidence demonstrating the safety of 5-ALA in the paediatric population. 5-ALA guided resection was found to be useful in the majority of cases but this did not correlate with GTR status. Ependymomas reliably fluoresce in 90% of cases, and 5-ALA-guided resection should be considered when a preoperative diagnosis of ependymoma is suspected.
Assuntos
Ácido Aminolevulínico/administração & dosagem , Ependimoma/cirurgia , Neoplasias Infratentoriais/cirurgia , Monitorização Neurofisiológica Intraoperatória/métodos , Meduloblastoma/cirurgia , Fármacos Fotossensibilizantes/administração & dosagem , Administração Oral , Ácido Aminolevulínico/metabolismo , Criança , Pré-Escolar , Ependimoma/diagnóstico por imagem , Ependimoma/metabolismo , Feminino , Humanos , Neoplasias Infratentoriais/diagnóstico por imagem , Neoplasias Infratentoriais/metabolismo , Masculino , Meduloblastoma/diagnóstico por imagem , Meduloblastoma/metabolismo , Imagem Óptica/métodos , Fármacos Fotossensibilizantes/metabolismoRESUMO
Ependymoma is the third most common pediatric tumor with posterior fossa group A (PFA) being its most aggressive subtype. Ependymomas are generally refractory to chemotherapies and thus lack any effective treatment. Here, we report that elevated expression of CXorf67 (chromosome X open reading frame 67), which frequently occurs in PFA ependymomas, suppresses homologous recombination (HR)-mediated DNA repair. Mechanistically, CXorf67 interacts with PALB2 and inhibits PALB2-BRCA2 interaction, thereby inhibiting HR repair. Concordantly, tumor cells with high CXorf67 expression levels show increased sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors, especially when combined with radiotherapy. Thus, our findings have revealed a role of CXorf67 in HR repair and suggest that combination of PARP inhibitors with radiotherapy could be an effective treatment option for PFA ependymomas.