Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas

Hartmann, Christian; Meyer, J.; Balß, Jörg; Capper, David; Mueller, Wolf; Christians, Arne; Felsberg, Jörg; Wolter, Marietta; Mawrin, Christian; Wick, Wolfgang; Weller, Michael; Herold‐Mende, Christel; Unterberg, Andreas; Jeuken, Judith; Wesseling, P.; Reifenberger, Guido; Deimling, Andreas von

doi:10.1007/s00401-009-0561-9

Cited by 1,040 publications

(863 citation statements)

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“…Only samples showing a RNA integrity number of 7 or more were used for microarray analyses. Mutational analyses of the IDH1, IDH2, TERT, BRAF and H3F3A genes were carried out by Sanger sequencing or pyrosequencing [9, 12,19]. The MGMT promoter methylation status was determined by methylation-specific PCR [8].…”

Section: Nucleic Acid Extraction Mutation and Promoter Methylation Amentioning

confidence: 99%

Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups

et al. 2015

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Cerebral gliomas of World Health Organization (WHO) grade II and III represent a major challenge in terms of histological classification and clinical management. Here, we asked whether largescale genomic and transcriptomic profiling improves the definition of prognostically distinct entities. We performed microarray-based genome-and transcriptome-wide analyses of primary tumor samples from a prospective German Glioma Network cohort of 137 patients with cerebral gliomas, including 61 WHO grade II and 76 WHO grade III tumors. Integrative bioinformatic analyses were employed to define molecular subgroups, which were then related to histology, molecular biomarkers, including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q co-deletion and telomerase reverse transcriptase (TERT) promoter mutations, and patient outcome. Genomic profiling identified five distinct glioma groups, including three IDH1/2 mutant and two IDH1/2 wild-type groups. Expression profiling revealed evidence for eight transcriptionally different groups (five IDH1/2 mutant, three IDH1/2 wild type), which were only partially linked to the genomic groups. Correlation of DNA-based molecular stratification with clinical outcome allowed to define three major prognostic groups with characteristic genomic aberrations. The best prognosis was found in patients with IDH1/2 mutant and 1p/19q co-deleted tumors. Patients with IDH1/2 wild-type gliomas and glioblastoma-like genomic alterations, including gain on chromosome arm 7q (+7q), loss on chromosome arm 10q (-10q), TERT promoter mutation and oncogene amplification, displayed the worst outcome. Intermediate survival was seen in patients with IDH1/2 mutant, but 1p/19q intact, mostly astrocytic gliomas, and in patients with IDH1/2 wild-type gliomas lacking the +7q/-10q genotype and TERT promoter mutation. This molecular subgrouping stratified patients into prognostically distinct groups better than histological classification. Addition of gene expression data to this genomic classifier did not further improve prognostic stratification. In summary, DNA-based molecular profiling of WHO grade II and III gliomas distinguishes biologically distinct tumor groups and provides prognostically relevant information beyond histological classification as well as IDH1/2 mutation and 1p/19q co-deletion status.

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Section: Nucleic Acid Extraction Mutation and Promoter Methylation Amentioning

confidence: 99%

Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups

et al. 2015

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“…For the amplification of a 129 bp fragment of the IDH1 gene and a 150 bp fragment of the IDH2 gene, spanning the respective sequence of the catalytic domains and codon 132 of IDH1 and codon 172 of IDH2, respectively, primers were used as previously published (Hartmann et al, 2009). IDH1-forward: 5 0 -CTCCTGATGAGAAGAGGGTTG-3 0 and IDH1-reverse: 5 0 -TGGAAATTTCTGGGCCATG-3 0 , IDH2-forward: 5 0 -TGGAACTATCCGGAACATCC-3 0 and IDH2-reverse: 5 0 -AGTCTGTGGCCTTGTACTGC-3 0 .…”

Section: Idh1 and Idh2 Mutation Analysismentioning

confidence: 99%

Epigenetic inactivation of the RASSF10 candidate tumor suppressor gene is a frequent and an early event in gliomagenesis

et al. 2010

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We have recently described the N-terminal RAS association domain family of genes, RASSF7-10. Previously, we cloned the N-terminal RASSF10 gene and demonstrated frequent methylation of the associated 5 0 -CpG island in acute lymphoblastic leukemia. To characterize RASSF10 gene expression, we demonstrate that in developing Xenopus embryos, RASSF10 shows a very striking pattern in the rhombencephalon (hind brain). It is also expressed in other parts of the brain and other organs. Due to the well-defined expression pattern in the brain of Xenopus embryos, we analyzed the methylation status of the RASSF10-associated 5 0 -CpG island in astrocytic gliomas. RASSF10 was frequently methylated in WHO grade II-III astrocytomas and WHO grade IV primary glioblastomas (67.5%), but was unmethylated in grade I astrocytomas and in DNA from age matched control brain samples. RASSF10 gene expression both at the mRNA and protein levels could be switched back on in methylated glioma cell lines after treatment with 5-aza-2 0 -deoxycytidine. In secondary glioblastomas (sGBM), RASSF10 methylation was an independent prognostic factor associated with worst progression-free survival and overall survival and occurred at an early stage in their development. In cell culture experiments, overexpression of RASSF10 mediated a reduction in the colony forming ability of two RASSF10-methylated glioma cell lines. Conversely, RNAi-mediated knockdown of RASSF10-stimulated anchorage-independent growth of U87 glioma cells, increased their viability and caused an increase in the cells' proliferative ability. We generated and characterized a RASSF10-specific antibody and demonstrated for the first time that RASSF10 subcellular localization is cell-cycle dependent with RASSF10 colocalizing to centrosomes and associated microtubules during mitosis. This is the first report demonstrating that RASSF10 can act as a tumor suppressor gene and is frequently methylated in gliomas and can potentially be developed into a prognostic marker for sGBM.

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“…Cytosolic isocitrate dehydrogenase 1 (IDH1) mutations were initially detected in a fraction of glioblastomas [14] followed by the observation that they are present in the majority of diffuse astrocytomas, oligodendrogliomas and mixed oligoastrocytomas of WHO grades II and III [1,7,9,22,26]. Consistently, the IDH1 mutation rate is also high in secondary glioblastoma developing from previously diagnosed astrocytoma.…”

Section: Introductionmentioning

confidence: 99%

Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas

et al. 2010

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provide evidence that the IDH1 status is more prognostic for overall survival than standard histological criteria that differentiate high-grade astrocytomas. We sequenced the isocitrate dehydrogenase 1 gene (IDH1) at codon 132 in 382 patients with anaplastic astrocytoma and glioblastoma from the NOA-04 trial and from a prospective translational cohort study of the German Glioma Network.Patients with anaplastic astrocytomas carried IDH1 mutations in 60%, and patients with glioblastomas in 7.2%. IDH1 was the most prominent single prognostic factor (RR=2.7; 95%-CI 1.6 to 4.5) followedby age, diagnosis and MGMT. The sequence from more favorable to poorer outcome was 1)anaplastic astrocytoma with IDH1 mutation, 2) glioblastoma with IDH1 mutation, 3) anaplastic astrocytoma without IDH1 mutation and 4) glioblastoma without IDH1 mutation (p<0.0001). In this combined set of anaplastic astrocytomas and glioblastomas both, IDH1 mutation and IDH1 expression status were of greater prognostic relevance than histological diagnosis according to the current WHO classification system. Our data indicate that much of the prognostic significance of patient age is due to the predominant occurrence of IDH1 mutations in younger patients. Immunohistochemistry using a mutation-specific antibody recognizing the R132H mutation yielded similar results. We propose to complement the current WHO classification and grading of high-grade astrocytic gliomas by the IDH1 mutation status and to use this combined histological and molecular classification in future clinical trials.

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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

Abstract: Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas

Cited by 1,040 publications

References 22 publications

Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups

Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups

Epigenetic inactivation of the RASSF10 candidate tumor suppressor gene is a frequent and an early event in gliomagenesis

Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: implications for classification of gliomas

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