Glioblastoma, the most aggressive and least treatable form of malignant glioma, is the most common human brain tumor. Although many regions of allelic loss occur in glioblastomas, relatively few tumor suppressor genes have been found mutated at such loci. To address the possibility that epigenetic alterations are an alternative means of glioblastoma gene inactivation, we coupled pharmacological manipulation of methylation with gene profiling to identify potential methylation-regulated, tumor-related genes. Triplicates of three short-term cultured glioblastomas were exposed to 5M 5-aza-dC for 96 hours followed by cRNA hybridization to an oligonucleotide microarray (Affymetrix U133A). We based candidate gene selection on bioinformatics, RT-PCR, bisulfite sequencing, methylation-specific PCR and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Two genes identified in this manner, RUNX3 and Testin (TES), were subsequently shown to harbor frequent tumor-specific epigenetic alterations in primary glioblastomas. This overall approach therefore provides a powerful means to identify candidate tumor suppressor genes for subsequent evaluation and may lead to the identification of genes whose epigenetic dysregulation is integral to glioblastoma tumorigenesis.
Downregulation of RUNX3 and TES by hypermethylation in glioblastoma.
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View SamplesTranscriptome analysis was performed from human U87 glioblastoma cell clones: U87 IRE1.NCK DN (U87dn, IRE1 dominant negative) and U87 control (U87ctrl, empty plasmid). Cells were grown in DMEM supplemented with 10% FBS and glutamine for 16 hours in culture prior mRNA isolation and analyses
Inositol-requiring enzyme 1alpha is a key regulator of angiogenesis and invasion in malignant glioma.
Cell line
View SamplesMutations in the enzymes IDH1 and IDH2 have been identified in a wide variety of tumors like glioma, chondrosarcoma, thyroid cancer, lymphoma, melanoma, and in acute myeloid leukemia. Mutated IDH1/2 produces the metabolite 2-hydroxyglutarate (2HG), which interferes with epigenetic regulation of gene expression, and thus may promote tumorigenesis.
Pan-mutant-IDH1 inhibitor BAY1436032 is highly effective against human IDH1 mutant acute myeloid leukemia in vivo.
Specimen part, Treatment
View SamplesEpendymal tumors across age groups have been classified and graded solely by histopathology. It is, however, commonly accepted that this classification scheme has limited clinical utility based on its lack of reproducibility in predicting patient outcome. We aimed at establishing a reliable molecular classification using DNA methylation fingerprints and gene expression data of the tumors on a large cohort of 500 tumors. Nine robust molecular subgroups, three in each anatomic compartment of the central nervous system (CNS), were identified.
Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups.
Sex, Specimen part
View SamplesGene expression profiling revealed over-representation of a distinct (proneural-like) expression signature in long-term survivors that was linked to IDH1/2 mutation. However, among the IDH1/2-wildtype patients, tumors from long-term survivors did not show distinct gene expression profiles and included proneural, classical and mesenchymal glioblastoma subtypes.
Molecular characterization of long-term survivors of glioblastoma using genome- and transcriptome-wide profiling.
Specimen part
View SamplesMolecular profiling of cerebral gliomas distinguishes biologically distinct tumor groups and provides prognostically relevant information beyond histological classification and IDH1/2 mutation status.
Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups.
Disease
View SamplesGene expression (mRNA) profiling of human ependymomas
Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma.
Sex, Age, Specimen part
View SamplesAryl hydrocarbon receptor (AHR) activation by tryptophan (Trp) catabolites enhances tumor malignancy and suppresses anti-tumor immunity. Hitherto, indoleamine-2,3-dioxygenase 1 (IDO1) or tryptophan- 2, 3-dioxygenase (TDO2) are recognized as the main Trp-catabolizing enzymes (TCEs) responsible for the generation of AHR agonists. Here, the ability of the aromatic L-amino acid oxidase, interleukin 4 induced 1 (IL4I1), to activate the AHR was investigated using IL4I1 knockout CAS-1 glioblastoma cells.
IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression.
Cell line
View SamplesAnalysis of the effect of IL4I1 on gene expression of CD8 T-cells in CLL
IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression.
Sex
View SamplesIndole-3-pyruvate (I3P), an endogenous metabolite derived from tryptophan by gut microbiota and IL4I1 enzyme in humans can potentially activate the transcriptional activity of the Aryl Hydrocarbon receptor. Here we test this by stimulating AHR proficient U-87MG cells with I3P alone or in combination with the AHR antagonist SR1.
IL4I1 Is a Metabolic Immune Checkpoint that Activates the AHR and Promotes Tumor Progression.
Cell line
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