We performed an integrative analysis to determine genomic aberrations common to sporadic schwannomas.
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PROVIDER: EGAS00001001886 | EGA |
REPOSITORIES: EGA
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Project description:Vestibular Schwannomas are benign neoplasms that arise from the vestibular nerve. The hallmark of these tumors is the biallelic inactivation of NF2. Transcriptomic alterations, such as the Nrg1/ErbB2 pathway, have been described in Schwannomas. Here, we have performed a whole transcriptomic analysis in 31 vestibular Schwannomas and 9 control nerves in the Affymetrix Gene 1.0ST platform, validated by quantitative Real-Time PCR using TaqMan Low Density Arrays. We performed a mutational analysis of NF2 by PCR/dHPLC and MLPA as well as a microsatellite marker analysis of the loss of heterozygosity of chromosome 22q. The microarray analysis showed that 1516 genes were deregulated, and 48 of the genes were validated by qRT-PCR. At least two genetic hits (allelic loss and/or gene mutation) in NF2 were found in 16 tumors, seven cases showed one hit and eight tumors showed no NF2 alteration. As conclusion, MET and associated genes such as ITGA4/B6, PLEXNB3/SEMA5 and CAV1 showed a clear deregulation in vestibular Schwannomas. In addition, androgen receptor (AR) downregulation may denote a hormonal effect or cause in this tumor. Furthermore, the osteopontin gene (SPP1), which is involved in Merlin protein degradation, was upregulated, which suggests that this mechanism may also exert a pivotal role in Schwannoma Merlin depletion. Finally, no major differences were found between tumors of different sizes, histological types or NF2 status, which suggests that at the mRNA level all Schwannomas, regardless of molecular and clinical characteristics, may share common features that can be used in the fight against them. In order to find target to fight against vestibular schwannoma, we performed an analysis of gene expression by microarrays.
2013-03-01 | E-GEOD-39645 | biostudies-arrayexpress
Project description:Vestibular Schwannomas are benign neoplasms that arise from the vestibular nerve. The hallmark of these tumors is the biallelic inactivation of NF2. Transcriptomic alterations, such as the Nrg1/ErbB2 pathway, have been described in Schwannomas. Here, we have performed a whole transcriptomic analysis in 31 vestibular Schwannomas and 9 control nerves in the Affymetrix Gene 1.0ST platform, validated by quantitative Real-Time PCR using TaqMan Low Density Arrays. We performed a mutational analysis of NF2 by PCR/dHPLC and MLPA as well as a microsatellite marker analysis of the loss of heterozygosity of chromosome 22q. The microarray analysis showed that 1516 genes were deregulated, and 48 of the genes were validated by qRT-PCR. At least two genetic hits (allelic loss and/or gene mutation) in NF2 were found in 16 tumors, seven cases showed one hit and eight tumors showed no NF2 alteration. As conclusion, MET and associated genes such as ITGA4/B6, PLEXNB3/SEMA5 and CAV1 showed a clear deregulation in vestibular Schwannomas. In addition, androgen receptor (AR) downregulation may denote a hormonal effect or cause in this tumor. Furthermore, the osteopontin gene (SPP1), which is involved in Merlin protein degradation, was upregulated, which suggests that this mechanism may also exert a pivotal role in Schwannoma Merlin depletion. Finally, no major differences were found between tumors of different sizes, histological types or NF2 status, which suggests that at the mRNA level all Schwannomas, regardless of molecular and clinical characteristics, may share common features that can be used in the fight against them.
2013-03-01 | GSE39645 | GEO
Project description:Background: Neurofibromatosis type 2 (NF2) is an autosomal dominant genetic disease characterized by the development of multiple Schwannomas, usually occurring on both VIIIth (vestibular) cranial nerves. Bromodomain and extra-terminal domain (BET) proteins regulate gene transcription and their activity is required in a variety of cancers including malignant peripheral nerve sheath tumors (MPNST). The use of BET inhibitors as a therapeutic option to treat NF2 schwannomas has not been explored and is the focus of this study. Methods: A panel of normal and NF2-null Schwann cell and schwannoma cell lines were used to characterize the impact of the BET inhibitor JQ1 in vitro and in vivo. The mechanism of action was explored by chromatin immunoprecipitation (ChIP) of the BET BRD4, phospho-kinase arrays and immunohistochemistry of BRD4 in human vestibular schwannomas. Results: JQ1 inhibited the proliferation of NF2-null schwannoma and Schwann cell lines in vitro and in vivo. Further, loss of NF2 by CRISPR deletion or siRNA knockdown increased the sensitivity of cells to JQ1. Knock-down experiments identified BRD4 as the BET family member mediating the majority of JQ1 effects on cell proliferation. Immunohistochemistry demonstrated elevated levels of BRD4 protein in human vestibular schwannomas. BRD4 ChIP experiments identified the small G-protein Rac1 and PI3K signaling pathways as sensitive to JQ1. Conclusions: NF2 deficient Schwann cell and schwannoma cells are sensitive to BET inhibition, primarily mediated by BRD4, which is overexpressed in human vestibular schwannomas. BRD4 regulates Rac/Ras and PI3K signaling pathways and inhibition of these pathways by JQ1 impedes NF2 Schwannoma growth. These findings implicate BET inhibition as a therapeutic option for NF2-deficient schwannomas.
2022-08-02 | GSE167560 | GEO
Project description:Treatment of multiple intracranial schwannomas in patient with neurofibromatosis type 2 (NF2) is extremely unsatisfactory and innovative therapeutic approaches are urgently needed. The lack of clinically relevant NF2 models has severely hampered drug discovery in this rare disease. Here, we report for the first time the establishment and characterization of patient-derived xenograft (PDX) and cell line models of NF2-associated schwannoma, which retain the gene mutations and transcriptome profile, and recapitulate the morphological and histopathological features with the patient tumors, retain patient NF2 mutations, and maintain gene expression profiles resembling the patient tumor profiles with the preservation of multiple key signaling pathways commonly dysregulated in human schwannoma. Using expression profiling, we found that the PI3K/AKT/mTOR networks are elevated in NF2-associated vestibular schwannomas, as well as in PDX models.
2022-04-04 | GSE180338 | GEO
Project description:Background: Schwannomas and grade I meningiomas are non-metastatic neoplasms that shares the common mutation of gene NF2. They usually appear in Neurofibromatosis type 2 patients. Currently, there is no drug treatment available for both tumors, so the use of wide expression technologies is crucial to find those therapeutic targets. Methodology: Affymetrix Human Gene 1.0 ST was used to test global gene expression in 22 meningiomas, 31 schwannomas and, as non-tumoral controls, 3 healthy meningeal tissues, 8 non-tumoral nerves and 1 primary Schwann cells culture. A non-stringent P-cutoff and fold change were used to establish deregulated genes. Results and discussion: We found a subset of genes that were upregulated in meningiomas and schwannomas when compared to their respectively healthy tissue, including PDGFD, CDH1, SLIT2 and MET. Thus, those genes could be more thoroughly studied as targets in a possible combined treatment. Methodology: Affymetrix Human Gene 1.0 ST was used to test global gene expression in 22 meningiomas, 31 schwannomas and, as non-tumoral controls, 3 healthy meningeal tissues, 8 non-tumoral nerves and 1 primary Schwann cells culture. A non-stringent P-cutoff and fold change were used to establish deregulated genes.
2015-08-30 | E-GEOD-54934 | biostudies-arrayexpress
Project description:Genome-wide DNA methylation profiling of 22 schwannomas belonging to three different genotypes (NF2-mutant, SOX10-mutant, and HTRA1-fused). 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 22 schwannomas.
2023-07-13 | GSE197094 | GEO
Project description:Background: Schwannomas and grade I meningiomas are non-metastatic neoplasms that shares the common mutation of gene NF2. They usually appear in Neurofibromatosis type 2 patients. Currently, there is no drug treatment available for both tumors, so the use of wide expression technologies is crucial to find those therapeutic targets. Methodology: Affymetrix Human Gene 1.0 ST was used to test global gene expression in 22 meningiomas, 31 schwannomas and, as non-tumoral controls, 3 healthy meningeal tissues, 8 non-tumoral nerves and 1 primary Schwann cells culture. A non-stringent P-cutoff and fold change were used to establish deregulated genes. Results and discussion: We found a subset of genes that were upregulated in meningiomas and schwannomas when compared to their respectively healthy tissue, including PDGFD, CDH1, SLIT2 and MET. Thus, those genes could be more thoroughly studied as targets in a possible combined treatment.
2015-08-30 | GSE54934 | GEO
Project description:Vestibular schwannomas are intracranial tumors that affects unilateral and sporadically or bilateral when is associated to Neurofibromatosis type 2 syndrome. The hallmark of the disease is the biallelic inactivation by NF2 gene mutation or LOH of chromosome 22q, where this gene harbors. In this work, we used Infinium HumanMethylation 450K BeadChip microarrays in a series of 36 vestibular schwannomas, 4 non-vestibular schwannomas and 5 healthy nerves. Our results shows a trend to hypomethylation in schwannomas. Furthermore, HOX genes, located at 4 clusters in the genome, displayed hypomethylation in numerous CpG sites in vestibular but not in non-vestibular schwannomas. Additionally, several microRNA and protein-coding genes were found hypomethylated at promoter regions and confirmed by expression analysis; including miRNA-199a1, miRNA-21, MET and PMEPA1. We also detected methylation patterns that might be involved in alternative transcripts of several genes such as NRXN1 or MBP; that would increase the complexity of methylation-expression. Overall, our results shows specific epigenetic signatures in several coding genes and microRNA that could be used in the finding of potential therapeutic targets.
2014-11-30 | GSE56597 | GEO
Project description:Vestibular schwannomas are intracranial tumors that affects unilateral and sporadically or bilateral when is associated to Neurofibromatosis type 2 syndrome. The hallmark of the disease is the biallelic inactivation by NF2 gene mutation or LOH of chromosome 22q, where this gene harbors. In this work, we used Infinium HumanMethylation 450K BeadChip microarrays in a series of 36 vestibular schwannomas, 4 non-vestibular schwannomas and 5 healthy nerves. Our results shows a trend to hypomethylation in schwannomas. Furthermore, HOX genes, located at 4 clusters in the genome, displayed hypomethylation in numerous CpG sites in vestibular but not in non-vestibular schwannomas. Additionally, several microRNA and protein-coding genes were found hypomethylated at promoter regions and confirmed by expression analysis; including miRNA-199a1, miRNA-21, MET and PMEPA1. We also detected methylation patterns that might be involved in alternative transcripts of several genes such as NRXN1 or MBP; that would increase the complexity of methylation-expression. Overall, our results shows specific epigenetic signatures in several coding genes and microRNA that could be used in the finding of potential therapeutic targets.
2014-11-30 | GSE56596 | GEO
Project description:Introduction: Meningiomas are the most common primary central nervous system (CNS) tumor in adults, comprising one-third of all primary adult CNS tumors. Although several recent publications have identified molecular alterations in meningioma including characteristic mutations, copy number alterations, and gene expression signatures, our understanding of the drivers of meningioma recurrence is limited. Objective: To identify gene expression signatures of 1p-22q-NF2- meningioma recurrence, with concurrent biallelic inactivation of NF2 and loss of chr1p that are heterogenous but enriched for recurrent meningiomas. Methods: Transcriptomic alterations present in recurrent versus primary 1p-22q-NF2- meningiomas were identified using RNA sequencing (RNA-seq) data in a clinically annotated cohort. Results: Recurrent 1p-22q-NF2- meningiomas were enriched for a newly identified GSTM1 null genotype compared to primary meningiomas that showed variable GSTM1 expression and independent external validation was performed. Conclusions: The GSTM1 null genotype is a novel biomarker of 1p-22q-NF2- meningioma recurrence that resolves heterogeneity in existing meningioma subtypes and may be used to guide future clinical management decisions on extent of treatment to improve patient outcomes.
2024-12-09 | GSE283616 | GEO