The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Xiuwu Bian - One of the best experts on this subject based on the ideXlab platform.
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isolation and characterization of stem cell like precursor cells from primary human anaplastic Oligoastrocytoma
Modern Pathology, 2007Co-Authors: Zhihua Zhou, Yifang Ping, Jianhong Chen, Xiaohong Yao, Hua Feng, Ji Ming Wang, Xiuwu BianAbstract:A small population of stem cell-like precursors in solid tumors are linked to histological composition, progression, angiogenesis, metastasis, recurrence and drug resistance of a variety of malignant tumors. Oligoastrocytoma is the most common brain mixed glioma composed of mixed cells of oligodendroglial and astrocytic phenotypes. Identification and characterization of stem cell-like precursors in Oligoastrocytoma may shed light on the oncogenesis of this unique type of tumor and assist in the design of novel therapeutic strategy. Here, tumor stem cell-like precursors were identified from primary human anaplastic Oligoastrocytomas by labeling of the tumor sections with nestin and CD133. Tumor cells were cultured in vitro in stem cell medium with growth factors and the capacity of the surviving stem cell-like precursors to form tumor spheres was tested. The tumor spheres were further injected subcutaneously into nude mice to observe the contribution of stem cell-like precursors to histological composition and tumor progression. We found that primary human Oligoastrocytoma tissues contained nestin+/CD133+ stem cell-like precursors. These cells differentiated into tumor cells with both oligodendroglial and astrocytic characteristics and formed tumor spheres in vitro, which upon implantation in nude mice, grew into tumor nodules containing nestin +/CD133+ cells at levels higher than in the primary tumor tissues. This study revealed for the first time that anaplastic human Oligoastrocytomas contained stem cell-like precursors, which exhibit neural stem cell properties with tumorigenicity. These stem cell-like precursors may be responsible for the oligodendroglial and astrocytic components of human Oligoastrocytoma and should be considered as therapeutic targets.
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isolation and characterization of stem cell like precursor cells from primary human anaplastic Oligoastrocytoma
Modern Pathology, 2007Co-Authors: Liang Yi, Zhihua Zhou, Yifang Ping, Jianhong Chen, Hua Feng, Ji Ming Wang, Jiayou Lu, Xiuwu BianAbstract:Isolation and characterization of stem cell-like precursor cells from primary human anaplastic Oligoastrocytoma
David Capper - One of the best experts on this subject based on the ideXlab platform.
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atrx and idh1 r132h immunohistochemistry with subsequent copy number analysis and idh sequencing as a basis for an integrated diagnostic approach for adult astrocytoma oligodendroglioma and glioblastoma
Acta Neuropathologica, 2015Co-Authors: Benedikt Wiestler, Daniel Schrimpf, David E Reuss, Felix Sahm, David CapperAbstract:Diffuse gliomas are represented in the 2007 WHO classification as astrocytomas, Oligoastrocytomas and oligodendrogliomas of grades II and III and glioblastomas WHO grade IV. Molecular data on these tumors have a major impact on prognosis and therapy of the patients. Consequently, the inclusion of molecular parameters in the WHO definition of brain tumors is being planned and has been forwarded as the “ISN-Haarlem” consensus. We, here, analyze markers of special interest including ATRX, IDH and 1p/19q codeletion in a series of 405 adult patients. Among the WHO 2007 classified tumors were 152 astrocytomas, 61 oligodendrogliomas, 63 Oligoastrocytomas and 129 glioblastomas. Following the concepts of the “ISN-Haarlem”, we rediagnosed the series to obtain “integrated” diagnoses with 155 tumors being astrocytomas, 100 oligodendrogliomas and 150 glioblastomas. In a subset of 100 diffuse gliomas from the NOA-04 trial with long-term follow-up data available, the “integrated” diagnosis had a significantly greater prognostic power for overall and progression-free survival compared to WHO 2007. Based on the “integrated” diagnoses, loss of ATRX expression was close to being mutually exclusive to 1p/19q codeletion, with only 2 of 167 ATRX-negative tumors exhibiting 1p/19q codeletion. All but 4 of 141 patients with loss of ATRX expression and diffuse glioma carried either IDH1 or IDH2 mutations. Interestingly, the majority of glioblastoma patients with loss of ATRX expression but no IDH mutations exhibited an H3F3A mutation. Further, all patients with 1p/19 codeletion carried a mutation in IDH1 or IDH2. We present an algorithm based on stepwise analysis with initial immunohistochemistry for ATRX and IDH1-R132H followed by 1p/19q analysis followed by IDH sequencing which reduces the number of molecular analyses and which has a far better association with patient outcome than WHO 2007.
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integrated dna methylation and copy number profiling identify three clinically and biologically relevant groups of anaplastic glioma
Acta Neuropathologica, 2014Co-Authors: Benedikt Wiestler, David Capper, Martin Sill, David T W Jones, Volker Hovestadt, Dominik Sturm, Christian Koelsche, Anna Marta Maria BertoniAbstract:The outcome of patients with anaplastic gliomas varies considerably. Whether a molecular classification of anaplastic gliomas based on large-scale genomic or epigenomic analyses is superior to histopathology for reflecting distinct biological groups, predicting outcomes and guiding therapy decisions has yet to be determined. Epigenome-wide DNA methylation analysis, using a platform which also allows the detection of copy-number aberrations, was performed in a cohort of 228 patients with anaplastic gliomas (astrocytomas, Oligoastrocytomas, and oligodendrogliomas), including 115 patients of the NOA-04 trial. We further compared these tumors with a group of 55 glioblastomas. Unsupervised clustering of DNA methylation patterns revealed two main groups correlated with IDH status: CpG island methylator phenotype (CIMP) positive (77.5 %) or negative (22.5 %). CIMPpos (IDH mutant) tumors showed a further separation based on copy-number status of chromosome arms 1p and 19q. CIMPneg (IDH wild type) tumors showed hallmark copy-number alterations of glioblastomas, and clustered together with CIMPneg glioblastomas without forming separate groups based on WHO grade. Notably, there was no molecular evidence for a distinct biological entity representing anaplastic Oligoastrocytoma. Tumor classification based on CIMP and 1p/19q status was significantly associated with survival, allowing a better prediction of outcome than the current histopathological classification: patients with CIMPpos tumors with 1p/19q codeletion (CIMP-codel) had the best prognosis, followed by patients with CIMPpos tumors but intact 1p/19q status (CIMP-non-codel). Patients with CIMPneg anaplastic gliomas (GBM-like) had the worst prognosis. Collectively, our data suggest that anaplastic gliomas can be grouped by IDH and 1p/19q status into three molecular groups that show clear links to underlying biology and a significant association with clinical outcome in a prospective trial cohort.
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mutation specific idh1 antibody differentiates oligodendrogliomas and Oligoastrocytomas from other brain tumors with oligodendroglioma like morphology
Acta Neuropathologica, 2011Co-Authors: David E Reuss, Jens Schittenhelm, Juliane Bremer, Felix Sahm, David Capper, Christian Hartmann, Patrick N HarterAbstract:Isocitrate dehydrogenase 1 (IDH1) mutations are frequent in astrocytomas, Oligoastrocytomas and oligodendrogliomas. We previously reported the generation of a mutation-specific antibody that specifically detects R132H mutated IDH1 protein (clone H09). Here, we investigate the feasibility of H09 immunohistochemistry to differentiate between oligodendrogliomas/Oligoastrocytomas and other tumors with similar morphology. A total of 274 brain tumors presenting with focal or extensive clear cell morphology were investigated. High numbers of H09-positive cases were observed in adult grade II oligodendrogliomas (67 of 74, 91%), grade III oligodendrogliomas (65 of 69, 94%), grade II Oligoastrocytomas (11 of 14, 79%) and grade III Oligoastrocytomas (10 of 11, 91%). All cases of pediatric oligodendrogliomas (n = 7), neurocytomas (n = 41, 35 central, 4 extraventricular, 2 cerebellar liponeurocytomas), dysembryoplastic neuroepithelial tumors (n = 21), clear cell ependymomas (n = 8), clear cell meningiomas (n = 9) as well as 12 primary glioblastomas with oligodendroglial differentiation and 5 pilocytic astrocytomas with oligodendroglial-like differentiation were negative for H09 immunohistochemistry. Three oligodendrogliomas with neurocytic differentiation had evidence of IDH1/IDH2 mutations either by H09 immunohistochemistry or direct sequencing. We conclude that in tumors with an oligodendroglioma-like morphology, binding of H09 is highly specific for oligodendrogliomas or Oligoastrocytomas and substantially helps in the discrimination from other clear cell tumors. Negative H09 immunohistochemistry of an adult oligodendroglioma or Oligoastrocytoma should prompt the consideration of other clear cell neoplasms. Further, our observations firmly assign oligodendrogliomas with neurocytic differentiation to the group of oligodendrogliomas and demonstrate that H09 is especially helpful for the difficult discrimination of such lesions from extraventricular neurocytomas.
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Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas
Acta Neuropathologica, 2009Co-Authors: Christian Hartmann, Jorg Felsberg, David Capper, Marietta Wolter, Jochen Meyer, Arne Christians, Jörg Balss, Wolf Mueller, Christian Mawrin, Wolfgang WickAbstract: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.
Andreas Von Deimling - One of the best experts on this subject based on the ideXlab platform.
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analysis of the idh1 codon 132 mutation in brain tumors
Acta Neuropathologica, 2008Co-Authors: Jörg Balss, Christian Hartmann, Jochen Meyer, Wolf Mueller, Andreas Von Deimling, Andrey KorshunovAbstract:A recent study reported on mutations in the active site of the isocitrate dehydrogenase (IDH1) gene in 12% of glioblastomas. All mutations detected resulted in an amino acid exchange in position 132. We analyzed the genomic region spanning wild type R132 of IDH1 by direct sequencing in 685 brain tumors including 41 pilocytic astrocytomas, 12 subependymal giant cell astrocytomas, 7 pleomorphic xanthoastrocytomas, 93 diffuse astrocytomas, 120 adult glioblastomas, 14 pediatric glioblastomas, 105 oligodendrogliomas, 83 Oligoastrocytomas, 31 ependymomas, 58 medulloblastomas, 9 supratentorial primitive neuroectodermal tumors, 17 schwannomas, 72 meningiomas and 23 pituitary adenomas. A total of 221 somatic IDH1 mutations were detected and the highest frequencies occurred in diffuse astrocytomas (68%), oligodendrogliomas (69%), Oligoastrocytomas (78%) and secondary glioblastomas (88%). Primary glioblastomas and other entities were characterized by a low frequency or absence of mutations in amino acid position 132 of IDH1. The very high frequency of IDH1 mutations in WHO grade II astrocytic and oligodendroglial gliomas suggests a role in early tumor development.
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shared allelic losses on chromosomes 1p and 19q suggest a common origin of oligodendroglioma and Oligoastrocytoma
Journal of Neuropathology and Experimental Neurology, 1995Co-Authors: Jurgen Kraus, Jens Koopmann, Peter Kaskel, David N Louis, Otmar D Wiestler, Sebastian Brandner, David Maintz, Johannes Schramm, Andreas Von DeimlingAbstract:Loss of heterozygosity (LOH) in specific chromosomal regions, which are likely to harbor tumor suppressor genes, has been associated with human gliomas. In this study we have analyzed astrocytic and oligodendroglial tumors for LOH on chromosomes 1 and 19. By microsatellite analysis LOH was found on chromosome arm 1p in 6/15 oligodendrogliomas WHO grade II and III, 12/25 Oligoastrocytomas WHO grade II and III, 6/79 glioblastomas WHO grade IV, 5/44 astrocytomas WHO grade II and III and 0/23 pilocytic astrocytomas WHO grade I. The high incidence of LOH on chromosome arm 1p in oligodendrogliomas and Oligoastrocytomas indicates that a putative tumor suppressor gene in this region is involved in the formation of gliomas with oligodendroglial features. Furthermore, the frequent involvement of chromosome arm 1p in oligodendrogliomas and Oligoastrocytomas, but not in astrocytomas, suggests that genetically Oligoastrocytoma is more similar to oligodendroglioma than to astrocytoma. In order to support this hypothesis, oligodendroglial and astrocytic areas in three mixed Oligoastrocytomas were examined differentially for LOH 1p and for LOH 19q, the second genetic region believed to be affected in these tumors. All three tumors had LOH of 1p and LOH of 19q in both areas of oligodendroglial and of astrocytic differentiation. These findings show that the astrocytic and oligodendroglial portions of Oligoastrocytoma share molecular genetic features and probably are of monoclonal origin.
Zhihua Zhou - One of the best experts on this subject based on the ideXlab platform.
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isolation and characterization of stem cell like precursor cells from primary human anaplastic Oligoastrocytoma
Modern Pathology, 2007Co-Authors: Zhihua Zhou, Yifang Ping, Jianhong Chen, Xiaohong Yao, Hua Feng, Ji Ming Wang, Xiuwu BianAbstract:A small population of stem cell-like precursors in solid tumors are linked to histological composition, progression, angiogenesis, metastasis, recurrence and drug resistance of a variety of malignant tumors. Oligoastrocytoma is the most common brain mixed glioma composed of mixed cells of oligodendroglial and astrocytic phenotypes. Identification and characterization of stem cell-like precursors in Oligoastrocytoma may shed light on the oncogenesis of this unique type of tumor and assist in the design of novel therapeutic strategy. Here, tumor stem cell-like precursors were identified from primary human anaplastic Oligoastrocytomas by labeling of the tumor sections with nestin and CD133. Tumor cells were cultured in vitro in stem cell medium with growth factors and the capacity of the surviving stem cell-like precursors to form tumor spheres was tested. The tumor spheres were further injected subcutaneously into nude mice to observe the contribution of stem cell-like precursors to histological composition and tumor progression. We found that primary human Oligoastrocytoma tissues contained nestin+/CD133+ stem cell-like precursors. These cells differentiated into tumor cells with both oligodendroglial and astrocytic characteristics and formed tumor spheres in vitro, which upon implantation in nude mice, grew into tumor nodules containing nestin +/CD133+ cells at levels higher than in the primary tumor tissues. This study revealed for the first time that anaplastic human Oligoastrocytomas contained stem cell-like precursors, which exhibit neural stem cell properties with tumorigenicity. These stem cell-like precursors may be responsible for the oligodendroglial and astrocytic components of human Oligoastrocytoma and should be considered as therapeutic targets.
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isolation and characterization of stem cell like precursor cells from primary human anaplastic Oligoastrocytoma
Modern Pathology, 2007Co-Authors: Liang Yi, Zhihua Zhou, Yifang Ping, Jianhong Chen, Hua Feng, Ji Ming Wang, Jiayou Lu, Xiuwu BianAbstract:Isolation and characterization of stem cell-like precursor cells from primary human anaplastic Oligoastrocytoma
Christian Hartmann - One of the best experts on this subject based on the ideXlab platform.
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analysis of cic associated cpg island methylation in Oligoastrocytoma
Neuropathology and Applied Neurobiology, 2013Co-Authors: Felix Sahm, Christian Hartmann, Wolf Mueller, Ulrike Lass, Christel Heroldmende, A Von DeimlingAbstract:Aims Combined deletion of the whole chromosomal arms 1p and 19q is a frequent event in oligodendroglial tumours. Recent identification of recurrent mutations in CIC on 19q and FUBP1 on 1p and their mutational patterns suggest a loss of function of the respective proteins. Surprisingly, Oligoastrocytomas harbouring identical genetic characteristics regarding 1p/19q codeletion and frequent IDH1/2 mutations have been shown to carry CIC mutations in a significantly lower number of cases. The present study investigates whether epigenetic modification may result in silencing of CIC. Methods As IDH1/2 mutation-mediated DNA hypermethylation is a prominent feature of these tumours, we analysed a set of CIC wild-type Oligoastrocytomas and other diffuse gliomas with regard to 1p/19q status for presence of CIC-associated CpG island methylation by methylation-specific PCR. Results Both methylation-specific PCR and subsequent bisulphite-sequencing of selected cases revealed an unmethylated status in all samples. Conclusion Despite the hypermethylator phenotype in IDH1/2 mutant tumours and recent detection of gene silencing particularly on retained alleles in oligodendroglial tumours, hypermethylation of CIC-associated CpG islands does not provide an alternative mechanism of functional CIC protein abrogation.
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mutation specific idh1 antibody differentiates oligodendrogliomas and Oligoastrocytomas from other brain tumors with oligodendroglioma like morphology
Acta Neuropathologica, 2011Co-Authors: David E Reuss, Jens Schittenhelm, Juliane Bremer, Felix Sahm, David Capper, Christian Hartmann, Patrick N HarterAbstract:Isocitrate dehydrogenase 1 (IDH1) mutations are frequent in astrocytomas, Oligoastrocytomas and oligodendrogliomas. We previously reported the generation of a mutation-specific antibody that specifically detects R132H mutated IDH1 protein (clone H09). Here, we investigate the feasibility of H09 immunohistochemistry to differentiate between oligodendrogliomas/Oligoastrocytomas and other tumors with similar morphology. A total of 274 brain tumors presenting with focal or extensive clear cell morphology were investigated. High numbers of H09-positive cases were observed in adult grade II oligodendrogliomas (67 of 74, 91%), grade III oligodendrogliomas (65 of 69, 94%), grade II Oligoastrocytomas (11 of 14, 79%) and grade III Oligoastrocytomas (10 of 11, 91%). All cases of pediatric oligodendrogliomas (n = 7), neurocytomas (n = 41, 35 central, 4 extraventricular, 2 cerebellar liponeurocytomas), dysembryoplastic neuroepithelial tumors (n = 21), clear cell ependymomas (n = 8), clear cell meningiomas (n = 9) as well as 12 primary glioblastomas with oligodendroglial differentiation and 5 pilocytic astrocytomas with oligodendroglial-like differentiation were negative for H09 immunohistochemistry. Three oligodendrogliomas with neurocytic differentiation had evidence of IDH1/IDH2 mutations either by H09 immunohistochemistry or direct sequencing. We conclude that in tumors with an oligodendroglioma-like morphology, binding of H09 is highly specific for oligodendrogliomas or Oligoastrocytomas and substantially helps in the discrimination from other clear cell tumors. Negative H09 immunohistochemistry of an adult oligodendroglioma or Oligoastrocytoma should prompt the consideration of other clear cell neoplasms. Further, our observations firmly assign oligodendrogliomas with neurocytic differentiation to the group of oligodendrogliomas and demonstrate that H09 is especially helpful for the difficult discrimination of such lesions from extraventricular neurocytomas.
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Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas
Acta Neuropathologica, 2009Co-Authors: Christian Hartmann, Jorg Felsberg, David Capper, Marietta Wolter, Jochen Meyer, Arne Christians, Jörg Balss, Wolf Mueller, Christian Mawrin, Wolfgang WickAbstract: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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analysis of the idh1 codon 132 mutation in brain tumors
Acta Neuropathologica, 2008Co-Authors: Jörg Balss, Christian Hartmann, Jochen Meyer, Wolf Mueller, Andreas Von Deimling, Andrey KorshunovAbstract:A recent study reported on mutations in the active site of the isocitrate dehydrogenase (IDH1) gene in 12% of glioblastomas. All mutations detected resulted in an amino acid exchange in position 132. We analyzed the genomic region spanning wild type R132 of IDH1 by direct sequencing in 685 brain tumors including 41 pilocytic astrocytomas, 12 subependymal giant cell astrocytomas, 7 pleomorphic xanthoastrocytomas, 93 diffuse astrocytomas, 120 adult glioblastomas, 14 pediatric glioblastomas, 105 oligodendrogliomas, 83 Oligoastrocytomas, 31 ependymomas, 58 medulloblastomas, 9 supratentorial primitive neuroectodermal tumors, 17 schwannomas, 72 meningiomas and 23 pituitary adenomas. A total of 221 somatic IDH1 mutations were detected and the highest frequencies occurred in diffuse astrocytomas (68%), oligodendrogliomas (69%), Oligoastrocytomas (78%) and secondary glioblastomas (88%). Primary glioblastomas and other entities were characterized by a low frequency or absence of mutations in amino acid position 132 of IDH1. The very high frequency of IDH1 mutations in WHO grade II astrocytic and oligodendroglial gliomas suggests a role in early tumor development.
