Gene expression of pediatric brain tumors- medulloblastoma and ependymoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
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PROVIDER: E-MTAB-14259 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:The objective of this study was to identify differentially expressed and prognostically important genes in pediatric medulloblastoma and pediatric ependymoma by Affymetrix microarray analysis. Among the most discriminative genes, three members of the SOX transcription factor family were differentially expressed. Both SOX4 and SOX11 were significantly overexpressed in medulloblastoma (median, 11-fold and 5-fold, respectively) compared with ependymoma and normal cerebellum. SOX9 had greater expression in ependymoma (median, 16-fold) compared with normal cerebellum and medulloblastoma (p<0.001 for all comparisons). The differential expression of the SOX genes was confirmed at the protein level by immunohistochemical analysis. Survival analysis of the most discriminative probe sets for each subgroup showed that 35 and 13 probe sets were predictive of survival in patients with medulloblastoma and ependymoma, respectively. There was a trend toward better survival with increasing SOX4 expression in medulloblastoma. SOX9 expression was predictive for favorable outcome in ependymoma. The mRNA levels of BCAT1, a mediator of amino acid breakdown, were higher (median, 15-fold) in medulloblastoma patients with metastases compared with those without metastasized disease (p<0.01). However, the correlation between BCAT1 expression and metastatic medulloblastoma could not be confirmed at the protein level. The potential prognostic effect of the genes associated with outcome should be evaluated in ongoing studies using larger groups of patients. Furthermore, our findings support further analysis of the functional properties of the selected genes, especially SOX4 and BCAT1 for medulloblastoma and SOX9 for ependymoma, to evaluate the use of these genes as potential tumor markers, prognostic markers, and drug targets in pediatric brain tumors.
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Project description:Analysis of the dentate gyrus of amygdala electrical stimulation model of temporal lobe epilepsy. Results provide insight into the molecular mechanism underlying epileptogenesis. This study was designed to estimate changes in gene expression levels after 7 and 30 days after electrical stimulation of amygdala as a model of temporal lobe epilepsy. The advantage of this study is time matched control (sham operated animals sacrificed at the same age as stimulated animals).
2013-08-14 | E-GEOD-49849 | biostudies-arrayexpress
Project description:Proteomics based on high-resolution mass spectrometry (MS) is the tool of choice for the analysis of protein presence, modifications and interactions, with increasing emphasis on the examination of tumor tissues. Application of MS-based proteomics offers a detailed picture of tumor tissue characteristics, facilitating the appreciation of different tumor entities, whilst providing reliable and fast results for therapeutic marker targeting and prognostic factor assessment. Through use of the high analytical resolution of nano-high-pressure liquid chromatography (nanoHPLC) and the high resolution of an Orbitrap Elite mass spectrometer, the present study aimed to provide knowledge on the proteome of the generally unknown entity of pediatric ependymal tumors.Ten resected specimens of childhood ependymoma were analyzed through a one-dimensional (1D) nanoLC-MS/MS approach. Method optimization steps were undertaken for both the sample preparation/protein extraction procedure and LC parameters, aiming to achieve the highest possible identification rates.Following method optimization, each nanoLC-MS/MS run resulted in identification of more than 5,000 proteins and more than 25,000 peptides for every analyzed sample, thus detailing the greater part of the ependymoma proteome. Identified proteins were found to spread throughout all known tumor categories regarding their molecular function and subcellular localization.Through the proposed nanoLC-MS/MS method herein we report, for the firs time, the ependymoma proteome database. A large number of similarities regarding proteome content are revealed compared to other two pediatric brain tumor entities; astrocytomas and medulloblastomas. Furthermore, through our approach, the majority of currently proposed markers for ependymoma (e.g. nucleolin, nestin, Ki67 and laminin subunit A2) as well as all major key players of the phosphoinositide 3-kinase pathway (seemingly implicated in ependymoma), were definitely detected.
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Project description:Proteomics, through application of modern high-end mass spectrometric (MS) approaches, offers the advantage of in-depth analysis of cancer tissues regarding their protein composition. Pediatric brain tumor malignancies are scarcely approached by modern holistic technologies (e.g. genomics, proteomics) due to rarity of samples and most importantly difficulty in their collection. Ependymoma, is the third most common tumor in children and is thought to arise from ependymal cells in the wall of the cerebral ventricles or the spinal canal. Due to the heterogeneity of the disease its biological characteristics remain largely unknown and prognostic factors are basically based on clinical and histological criteria. Through application of a modified nanoLC-MS/MS analysis experimental approach we achieved, for the first time, the in-depth examination of the pediatric ependymoma tissue proteome. In the present article we report on the construction of a high-confidence database; the Pediatric Ependymoma Protein Database (PEPD), including 4,157 protein groups originating from the identification and analysis of more than 15,000 peptides. The PEPD offers a first step towards targeted protein validation of the protein content of this specific devastating disease affecting the young population.
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Project description:Mouse models of medulloblastoma have proven to be instrumental in understanding disease mechanisms, particularly the role of epigenetic and molecular drivers, and establishing appropriate preclinical pipelines. To date, our research community has developed murine models for all four groups of medulloblastoma, each of which will be critical for the identification and development of new therapeutic approaches. Approaches to modeling medulloblastoma range from genetic engineering with CRISPR/Cas9 or in utero electroporation, to orthotopic and patient-derived orthotopic xenograft systems. Each approach or model presents unique advantages that have ultimately contributed to an appreciation of medulloblastoma heterogeneity and the clinical obstacles that exist for this patient population.
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Project description:Myxopapillary ependymoma (MEPN) generally can be cured by gross total surgical resection and usually manifest a favorable prognosis. However, surgery is less curative in tumors that are large, multifocal or extend outside the thecal sac. Late recurrences may occur, particularly in pediatric patients. The role of adjuvant therapy is unclear in the clinical management of recurrent tumors. Clinical trial design requires a better understanding of tumor biology. Unique molecular features of MEPN were investigated by using microarray technology to compare the gene expression of five pediatric MEPN to 24 pediatric intracranial ependymoma (EPN). The upregulation of three genes of interest, homeobox B13 (HOXB13), neurofilament, light polypeptide (NEFL) and PDGFR alpha, was further studied by immunohistochemistry in a larger cohort that included adult MEPN and EPN specimens. Protein expression in MEPN was compared to subependymoma, spinal EPN, intracranial EPN and normal fetal and adult ependyma. Immunoreactivity for HOXB13, NEFL and PDGFR alpha was strongest in MEPN and virtually absent in subependymoma. Spinal and intracranial EPN generally expressed weak or focal staining. MEPN manifests unique gene and protein expression patterns compared to other EPNs. Aberrant expression of HOXB13 suggests possible recapitulation of developmental pathways in MEPN tumorigenesis. PDGFR alpha may be a potential therapeutic target in recurrent MEPN.
| S-EPMC2871180 | biostudies-literature
Project description:Children with medulloblastoma and ependymoma are treated with a multidisciplinary approach that incorporates surgery, radiotherapy, and chemotherapy; however, overall survival rates for patients with high-risk disease remain unsatisfactory. Data indicate that plant-derived cannabinoids are effective against adult glioblastoma; however, preclinical evidence supporting their use in pediatric brain cancers is lacking. Here we investigated the potential role for ?9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in medulloblastoma and ependymoma. Dose-dependent cytotoxicity of medulloblastoma and ependymoma cells was induced by THC and CBD in vitro, and a synergistic reduction in viability was observed when both drugs were combined. Mechanistically, cannabinoids induced cell cycle arrest, in part by the production of reactive oxygen species, autophagy, and apoptosis; however, this did not translate to increased survival in orthotopic transplant models despite being well tolerated. We also tested the combination of cannabinoids with the medulloblastoma drug cyclophosphamide, and despite some in vitro synergism, no survival advantage was observed in vivo. Consequently, clinical benefit from the use of cannabinoids in the treatment of high-grade medulloblastoma and ependymoma is expected to be limited. This study emphasizes the importance of preclinical models in validating therapeutic agent efficacy prior to clinical trials, ensuring that enrolled patients are afforded the most promising therapies available.
| S-EPMC7829707 | biostudies-literature
Project description:Medulloblastoma is the most common malignant brain tumor affecting children. These tumors are high grade with propensity to metastasize within the central nervous system and, less frequently, outside the neuraxis. Recent advancements in molecular subgrouping of medulloblastoma refine diagnosis and improve counseling in regards to overall prognosis. Both are predicated on the molecular drivers of each subgroup-WNT-activated, SHH-activated, group 3, and group 4. The traditional therapeutic mainstay for medulloblastoma includes a multimodal approach with surgery, radiation, and multiagent chemotherapy. As we discover more about the molecular basis of medulloblastoma, efforts to adjust treatment approaches based on molecular risk stratification are under active investigation. Certainly, the known neurological, developmental, endocrine, and psychosocial injury related to medulloblastoma and its associated therapies motivate ongoing research towards improving treatment for this life-threatening tumor while at the same time minimizing long-term side effects.
| S-EPMC5909805 | biostudies-literature
Project description:Epigenetics is the process by which gene expression is regulated by events other than alterations of the genome. This includes DNA methylation, histone modifications, chromatin remodeling, microRNAs, and long non-coding RNAs. Methylation of DNA, chromatin remodeling, and histone modifications regulate the chromatin and access of transcription factors to DNA and in turn gene transcription. Alteration of chromatin is now recognized to be deregulated in many cancers. Medulloblastoma is an embryonal tumor of the cerebellum and the most common malignant brain tumor in children, that occurs only rarely in adults. Medulloblastoma is characterized by four major molecularly and histopathologically distinct groups, wingless (WNT), sonic hedgehog (SHH), group 3 (G3), and group 4 (G4), that, except for WNT, are each now subdivided in several subgroups. Gene expression array, next-generation sequencing, and methylation profiling of several hundred primary tumors by several consortia and independent groups revealed that medulloblastomas harbor a paucity of mutations most of which occur in epigenetic regulators, genetic alterations in oncogenes and tumor suppressors, in addition to copy number alterations and chromosome gains and losses. Remarkably, some tumors have no reported mutations, suggesting that some genes required for oncogenesis might be regulated by epigenetic mechanisms which are still to be uncovered and validated. This review will highlight several epigenetic regulators focusing mainly on histone modifiers identified in medulloblastoma.
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Project description:This file contains the expression data for pediatric medulloblastomas and ependymomas
2015-10-21 | GSE74195 | GEO