Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0017638 (glioma)
30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Separation of pilocytic astrocytoma from diffuse astrocytomas frequently poses problems mostly related to small sample size. Precise classification and grading are essential due to different therapeutic strategies prompted by diagnoses of pilocytic astrocytoma WHO grade I, diffuse astrocytomas WHO grade II or anaplastic astrocytoma WHO grade III. Recently, genomic aberrations with a high specificity for distinct glioma entities have been described. Pilocytic astrocytomas carry a duplication at chromosome band 7q34 containing a BRAF-KIAA1549 gene fusion in the majority of cases. IDH1 mutations are observed very frequently in adult astrocytomas and IDH2 mutations have been reported in some astrocytomas. We examined a series of 120 astrocytomas including 70 pilocytic astrocytomas WHO grade I and 50 diffuse astrocytomas WHO grade II for both, BRAF-KIAA1549 fusion with a newly developed FISH assay and mutations in IDH1 and IDH2 by direct sequencing. Pilocytic astrocytomas contained the BRAF fusion in 49 cases (70%) but neither IDH1 nor IDH2 mutations. Astrocytomas WHO grade II exhibited IDH1 mutations in 38 cases (76%) but neither IDH2 mutations nor BRAF fusions. Thus, combined molecular analysis of BRAF and IDH1 is a sensitive and highly specific approach to separate pilocytic astrocytoma from diffuse astrocytoma.
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PMID:Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. 1954 40

Somatic mutations in the IDH1 gene encoding cytosolic NADP+-dependent isocitrate dehydrogenase have been shown in the majority of astrocytomas, oligodendrogliomas and oligoastrocytomas of WHO grades II and III. IDH2 encoding mitochondrial NADP+-dependent isocitrate dehydrogenase is also mutated in these tumors, albeit at much lower frequencies. Preliminary data suggest an importance of IDH1 mutation for prognosis showing that patients with anaplastic astrocytomas, oligodendrogliomas and oligoastrocytomas harboring IDH1 mutations seem to fare much better than patients without this mutation in their tumors. To determine mutation types and their frequencies, we examined 1,010 diffuse gliomas. We detected 716 IDH1 mutations and 31 IDH2 mutations. We found 165 IDH1 (72.7%) and 2 IDH2 mutations (0.9%) in 227 diffuse astrocytomas WHO grade II, 146 IDH1 (64.0%) and 2 IDH2 mutations (0.9%) in 228 anaplastic astrocytomas WHO grade III, 105 IDH1 (82.0%) and 6 IDH2 mutations (4.7%) in 128 oligodendrogliomas WHO grade II, 121 IDH1 (69.5%) and 9 IDH2 mutations (5.2%) in 174 anaplastic oligodendrogliomas WHO grade III, 62 IDH1 (81.6%) and 1 IDH2 mutations (1.3%) in 76 oligoastrocytomas WHO grade II and 117 IDH1 (66.1%) and 11 IDH2 mutations (6.2%) in 177 anaplastic oligoastrocytomas WHO grade III. We report on an inverse association of IDH1 and IDH2 mutations in these gliomas and a non-random distribution of the mutation types within the tumor entities. IDH1 mutations of the R132C type are strongly associated with astrocytoma, while IDH2 mutations predominantly occur in oligodendroglial tumors. In addition, patients with anaplastic glioma harboring IDH1 mutations were on average 6 years younger than those without these alterations.
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PMID:Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. 1955 37

A recent study reported on mutations in the active site of the isocitrate dehydrogenase 1 (IDH1) gene in several types of gliomas. All mutations detected resulted in an amino acid exchange at position 132. We analyzed the genomic region spanning wild-type R132 of IDH1 by direct sequencing in 125 glial tumors. A total of 39 IDH1 mutations were observed. Mutations of the IDH2 gene, homologous to IDH1, were often detected in gliomas without IDH1 mutations. In the present study, R172 mutation of the IDH2 gene was detected in one anaplastic astrocytoma. IDH1 or IDH2 mutations were frequently in oligodendrogliomas (67%), anaplastic astrocytomas (62%), anaplastic oligoastrocytomas (75%), anaplastic oligodendrogliomas (50%), secondary glioblastomas (67%), gangliogliomas (38%), and anaplastic gangliogliomas (60%). Primary glioblastomas were characterized by a low frequency of mutations (5%) at amino acid position 132 of IDH1. Mutations of the IDH1 or IDH2 genes were significantly associated with improved outcome in patients with anaplastic astrocytomas. Our data suggest that IDH1 or IDH2 mutation plays a role in early tumor progression of several types of glioma and might arise from a common glial precursor. The infrequency of IDH1 mutation in primary glioblastomas revealed that these subtypes are genetically distinct entities from other glial tumors.
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PMID:Analysis of IDH1 and IDH2 mutations in Japanese glioma patients. 1976

Mutations in isocitrate dehydrogenase enzyme isoforms 1 (IDH1) and 2 (IDH2) have been identified in many adult astrocytomas and oligodendrogliomas. These mutations are targeted to specific codons (e.g. R132 in IDH1 and R172 in IDH2), making assays to detect them in clinical specimens feasible. We describe a simple and accurate molecular assay for detection of IDH1/2 mutations on routine formalin-fixed paraffin-embedded tissues. Using this polymerase chain reaction-based assay, we tested 75 glial neoplasms and 57 nonneoplastic conditions that can mimic gliomas including radiation changes, viral infections, and infarcts. Of the gliomas, 37 (49%) were positive for IDH1 or IDH2 mutations; the most common mutation was IDH1 (97%). Two of 12 gangliogliomas were positive for IDH1 mutation, and both had unfavorable clinical outcomes (p < 0.03). None of the nonneoplastic cases were positive for IDH mutations. The assay detected IDH mutations in biopsy material containing mostly glioma and in concomitant near-miss stereotactic core biopsies that were otherwise equivocal for the presence of glioma by light microscopy. These results indicate that testing for IDH1/2 mutations can be effectively performed in a clinical setting and can enhance the accuracy of diagnosis of gliomas when traditional diagnostic methods are not definitive.
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PMID:Diagnostic use of IDH1/2 mutation analysis in routine clinical testing of formalin-fixed, paraffin-embedded glioma tissues. 2019 Jun 7

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), are present in most gliomas and secondary glioblastomas, but are rare in other neoplasms. IDH1/2 mutations are heterozygous, and affect a single arginine residue. Recently, IDH1 mutations were identified in 8% of acute myelogenous leukemia (AML) patients. A glioma study revealed that IDH1 mutations cause a gain-of-function, resulting in the production and accumulation of 2-hydroxyglutarate (2-HG). Genotyping of 145 AML biopsies identified 11 IDH1 R132 mutant samples. Liquid chromatography-mass spectrometry metabolite screening revealed increased 2-HG levels in IDH1 R132 mutant cells and sera, and uncovered two IDH2 R172K mutations. IDH1/2 mutations were associated with normal karyotypes. Recombinant IDH1 R132C and IDH2 R172K proteins catalyze the novel nicotinamide adenine dinucleotide phosphate (NADPH)-dependent reduction of alpha-ketoglutarate (alpha-KG) to 2-HG. The IDH1 R132C mutation commonly found in AML reduces the affinity for isocitrate, and increases the affinity for NADPH and alpha-KG. This prevents the oxidative decarboxylation of isocitrate to alpha-KG, and facilitates the conversion of alpha-KG to 2-HG. IDH1/2 mutations confer an enzymatic gain of function that dramatically increases 2-HG in AML. This provides an explanation for the heterozygous acquisition of these mutations during tumorigenesis. 2-HG is a tractable metabolic biomarker of mutant IDH1/2 enzyme activity.
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PMID:Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations. 2036 82

Novel mutations in the isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) genes have been identified in a large proportion of diffuse gliomas. Tumors with IDH1/2 mutations have distinctive clinical characteristics, including a less aggressive course. The aim of this study was to develop and evaluate the performance of a novel real-time PCR and post-PCR fluorescence melting curve analysis assay for the detection of IDH1 and IDH2 mutations in routine formalin-fixed, paraffin-embedded tissues of brain biopsies. Using the established assay, we tested 67 glial neoplasms, 57 non-neoplastic conditions that can often mimic gliomas (eg, radiation changes, viral infections, infarctions, etc), and 44 noncentral nervous system tumors. IDH1 and IDH2 mutations were detected in 72% of lower grade diffuse gliomas and in 17% of glioblastomas. The IDH1 mutation was the most common (93%), with the most frequent subtype being R132H (88%). These mutations were not identified in non-neoplastic glioma mimickers and in noncentral nervous system tumors including thyroid carcinomas. The results of this assay had a 100% correlation with the results obtained by conventional sequencing. In summary, we report here the real-time PCR/fluorescence melting curve analysis assay that provides rapid and sensitive detection of IDH mutations in formalin-fixed, paraffin-embedded tissues, and is therefore useful as a powerful adjunct diagnostic tool for refining histopathological diagnosis of brain lesions and guiding patient management.
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PMID:Detection of IDH1 and IDH2 mutations by fluorescence melting curve analysis as a diagnostic tool for brain biopsies. 2043 Oct 32

To identify novel glioma-associated pathomechanisms and molecular markers, we performed an array-based comparative genomic hybridization analysis of 131 diffuse astrocytic gliomas, including 87 primary glioblastomas (pGBIV), 13 secondary glioblastomas (sGBIV), 19 anaplastic astrocytomas (AAIII) and 12 diffuse astrocytomas (AII). All tumors were additionally screened for IDH1 and IDH2 mutations. Expression profiling was performed for 74 tumors (42 pGBIV, 11 sGBIV, 13 AAIII, 8 AII). Unsupervised and supervised bioinformatic analyses revealed distinct genomic and expression profiles separating pGBIV from the other entities. Classifier expression signatures were strongly associated with the IDH1 gene mutation status. Within pGBIV, the rare subtype of IDH1 mutant tumors shared expression profiles with IDH1 mutant sGBIV and was associated with longer overall survival compared with IDH1 wild-type tumors. In patients with IDH1 wild-type pGBIV, PDGFRA gain or amplification as well as 19q gain were associated with patient outcome. Array-CGH analysis additionally revealed homozygous deletions of the FGFR2 gene at 10q26.13 in 2 pGBIV, with reduced FGFR2 mRNA levels being frequent in pGBIV and linked to poor outcome. In conclusion, we report that diffuse astrocytic gliomas can be separated into 2 major molecular groups with distinct genomic and mRNA profiles as well as IDH1 gene mutation status. In addition, our results suggest FGFR2 as a novel glioma-associated candidate tumor suppressor gene on the long arm of chromosome 10.
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PMID:Molecular signatures classify astrocytic gliomas by IDH1 mutation status. 2047 36

Heterozygous mutations in either the R132 residue of isocitrate dehydrogenase I (IDH1) or the R172 residue of IDH2 in human gliomas were recently highlighted. Heterozygous mutations in the IDH1 occur in the majority of grade II and grade III gliomas and secondary glioblastomas and change the structure of the enzyme, which diminishes its ability to convert isocitrate (ICT) to alpha-ketoglutarate (alpha-KG) and provides it with a newly acquired ability to convert alpha-KG to R(-)-2-hydroxyglutarate [R(-)-2HG]. The IDH1 and IDH2 mutations are relevant to the progression of gliomas, the prognosis and treatment of the patients with gliomas harboring the mutation. In this paper, we reviewed these recent findings which were essential for the further exploration of human glioma cancer and might be responsible for developing a newer and more effective therapeutic approach in clinical treatment of this cancer.
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PMID:Glioma-derived mutations in IDH: from mechanism to potential therapy. 2051 Aug 84

The discovery of somatic mutations in the gene encoding isocitrate dehydrogenase-1 (IDH1) in glioblastomas was remarkable because the enzyme was not previously identified with any known oncogenic pathway. IDH1 is mutated in up to 75% of grade II and grade III diffuse gliomas. Apart from acute myeloid leukaemia, other tumour types do not carry IDH1 mutations. Mutations in a homologous gene, IDH2, have also been identified, although they are much rarer. Although TP53 mutations and 1p/19q codeletions are mutually exclusive in gliomas, in both of these genotypes IDH1 mutations are common. IDH1 and IDH2 mutations are early events in the development of gliomas. Moreover, IDH1 and IDH2 mutations are a major prognostic marker for overall and progression-free survival in grade II-IV gliomas. Mutated IDH1 has an altered catalytic activity that results in the accumulation of 2-hydroxyglutarate. Molecularly, IDH1 and IDH2 mutations are heterozygous, affect only a single codon, and rarely occur together. Because IDH1 does not belong to a traditional oncogenic pathway and is specifically and commonly mutated in gliomas, the altered enzymatic activity of IDH1 may provide a fundamentally new understanding of diffuse glioma.
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PMID:Isocitrate dehydrogenase-1 mutations: a fundamentally new understanding of diffuse glioma? 2061 53

The systematic sequencing of glioblastoma multiforme (GBM) genomes has identified the recurrent mutation of IDH1, a gene encoding NADP(+)-dependent isocitrate dehydrogenase 1 (IDH1) that catalyzes the oxidative decarboxylation of isocitrate yielding alpha-ketoglutarate (alpha-KG). Subsequent studies have confirmed recurrent IDH1 and IDH2 mutations in up to 70% of low-grade glioma and secondary GBM, as well as in 10% of acute myeloid leukemia (AML) cases. The heterozygous somatic mutations at arginine R132 (IDH1) and at R140 or R172 (IDH2) in the enzyme active site confer a gain of function to the enzymes, which can both produce the metabolite 2-hydroxyglutarate. This review surveys the prevalence of IDH mutations in cancer and explores current mechanistic understanding of IDH mutations with implications for diagnostic and therapeutic development for the treatment of gliomas and AML.
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PMID:IDH mutations in glioma and acute myeloid leukemia. 2069 6


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