Correlations Between O6-Methylguanine DNA Methyltransferase Promoter Methylation Status, 1p and 19q Deletions, and Response to Temozolomide in Anaplastic and Recurrent Oligodendroglioma: A Prospective GICNO Study

Brandes, Alba A.; Tosoni, Alicia; Cavallo, Giovanna; Reni, Michele; Franceschi, Enrico; Bonaldi, Laura; Bertorelle, Roberta; Gardiman, Marina Paola; Ghimenton, Claudio; Iuzzolino, P.; Pession, Annalisa; Blatt, V.; Ermani, Mario

doi:10.1200/jco.2006.06.3891

Cited by 169 publications

(104 citation statements)

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“…This contrasts with a German study, in which both IDH1 mutations and MGMT promoter methylation were independent prognostic variables, and in which analysis the presence of the 1p/19q codeletion lost its prognostic significance (20). Of note, combined loss of 1p/19q is also highly correlated with MGMT promoter methylation (5,21,22). Moreover, our current data and a previous report from our group confirm the presence of IDH1 mutations both in patients with the 1p/19q codeletion and with TP53 mutations, although in all the series, a substantial percentage of 1p/19q-codeleted or TP53-mutated tumors do not carry and IDH1 or IDH2 mutation (5,6,23).…”

Section: Discussioncontrasting

confidence: 49%

IDH1 and IDH2 Mutations Are Prognostic but not Predictive for Outcome in Anaplastic Oligodendroglial Tumors: A Report of the European Organization for Research and Treatment of Cancer Brain Tumor Group

Bent

Dubbink

Marie

et al. 2010

Clinical Cancer Research

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Purpose: Recent studies have shown the prognostic significance of IDH1 mutations in glioma. It is yet unclear if IDH1 mutations are predictive for outcome to chemotherapy. We determined the effect of IDH1 mutations on progression-free survival and overall survival (OS), and its correlation with other clinical and molecular features in the prospective randomized European Organization for Research and Treatment of Cancer study 26951 on adjuvant procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-L-nitrosourea, and vincristine (PCV) in anaplastic oligodendroglioma.Experimental Design: IDH1 and IDH2 alterations of the mutational hotspot codons R132 and R172 were assessed by the bidirectional cycle sequencing of PCR-amplified fragments. MGMT promoter methylation was assessed using methylation-specific multiplex ligation-dependant probe amplification based on methylation-sensitive restriction analysis. Loss of chromosomes 1p, 19q, 10, and 10q and the gain of 7 and the EGFR gene were assessed with fluorescence in situ hybridization.Results: From 159 patients, sufficient material was available for IDH1 analysis. In 151 and 118 of these patients, respectively, the 1p/19q status and the MGMT promoter methylation status were known. In 73 cases (46%), an IDH1 mutation was found and only one IDH2 mutation was identified. The presence of IDH1 mutations correlated with 1p/19q codeletion and MGMT promoter methylation, and inversely correlated with loss of chromosome 10, EGFR amplification, polysomy of chromosome 7, and the presence of necrosis. IDH1 mutations were found to be prognostic in the radiotherapy-and the radiotherapy/PCVtreated patients, for both progression-free survival and OS. With Cox proportional hazard modeling for OS with stepwise selection, IDH1 mutations and 1p/19q codeletion but not MGMT promoter methylation were independent prognostic factors.Conclusion: In this homogeneously treated group of anaplastic oligodendroglioma patients, the presence of IDH1 mutations was found to carry a very strong prognostic significance for OS but without evidence of a predictive significance for outcome to PCV chemotherapy. IDH1 mutations were strongly associated with 1p/ 19q codeletion and MGMT promoter methylation. Clin Cancer Res; 16(5); 1597-604. ©2010 AACR.

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Section: Discussioncontrasting

confidence: 49%

IDH1 and IDH2 Mutations Are Prognostic but not Predictive for Outcome in Anaplastic Oligodendroglial Tumors: A Report of the European Organization for Research and Treatment of Cancer Brain Tumor Group

Bent

Dubbink

Marie

et al. 2010

Clinical Cancer Research

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“…High frequency of 1p/19q deletions may reflect relatively strict histological criteria for oligodendroglioma in our laboratory. Data on the correlation between MGMT hypermethylation and 1p/19q deletion are controversial; some studies report a significant correlation between MGMT hypermethylation and isolated or combined 1p/ 19q LOH (Dong et al, 2001;Mollemann et al, 2005;Brandes et al, 2006;van den Bent et al, 2009; Yang et al, 2009), whereas others are unable to find a statistically significant relationship between them (Watanabe et al, 2002;Everhard et al, 2006;Kuo et al, 2009;Jha et al, 2010). We found a negative correlation between MGMT hypermethylation and 19q loss but no association was seen between MGMT and 1p loss or combined 1p/19q loss.…”

Section: Discussioncontrasting

confidence: 42%

“…An additional molecular marker for oligodendroglial tumors is the loss of chromosome arms 1p and 19q. Oligodendrogliomas with 1p/19q deletions are chemosensitive and have a more favorable prognosis (Cairncross et al, 1998;Brandes et al, 2006). Astrocytomas, especially glioblastomas, are characterized by a high incidence of mutations in the TP53 gene, loss of heterozygosity in chromosome arm 10q, EGFR gene amplification, CDKN2A deletion, and PTEN gene mutation .…”

Section: Introductionmentioning

confidence: 99%

The hypermethylation of the O⁶‐methylguanine‐DNA methyltransferase gene promoter in gliomas—correlation with array comparative genome hybridization results and IDH1 mutation

Tuononen

Tynninen

Sarhadi

et al. 2011

Genes Chromosomes & Cancer

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The use of molecular markers in the diagnostics of gliomas aids histopathological diagnosis and allows their further classification into clinically significant subgroups. The aim of this study was to characterize the methylation pattern of the O 6 -methylguanine-DNA methyltransferase (MGMT) promoter, gene copy number aberrations, and isocitrate dehydrogenase I (IDH1) mutation in gliomas. We studied 51 gliomas (15 oligodendrogliomas, 18 oligoastrocytomas, 3 astrocytomas, and 15 glioblastomas) by pyrosequencing, array comparative genome hybridization (CGH), and immunohistochemistry. MGMT hypermethylation was observed in 100% of oligoastrocytomas, 93% of oligodendrogliomas, and 47% of glioblastomas. The most frequently altered chromosomal regions were deletions of 1p31.1/21.1-22.2 and 19q13.3qter in oligodendroglial tumors, and losses of 9p21.3, 10q25.3qter, and 10q26.13-26.2 in glioblastomas. Deletions on 9p and 10q, and gain of 7p were associated with the unmethylated MGMT phenotype, whereas deletion of 19q and oligodendroglial morphology was associated with MGMT hypermethylation. IDH1 mutation showed positive correlation with MGMT hypermethylation and loss of 1p/19q. Our results suggest that MGMT promoter methylation, analyzed by pyrosequencing, is a frequent event in oligodendroglial tumors, and it correlates with IDH1 mutation and 19q loss in gliomas. Pyrosequencing proved a good method for assessing the degree of MGMT methylation in formalin-fixed paraffin-embedded glioma samples. However, further studies are needed to confirm a clinically relevant cut-off point for MGMT methylation in gliomas.

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“…In addition, we examined the MGMT and cyclooxygenase 2 (COX2), an isozyme of prostaglandinendoperoxidase synthase 2 (1q25.2q25.3) gene promoter methylation in these patients. MGMT is a gene of interest in high-grade gliomas, namely GBM, as the methylation of its promoter predicts chemosensitivity to alkylating agents; it is also under evaluation in low-grade gliomas (11)(12)(13)23). The COX2 gene promoter methylation provides epigenetic information regarding genetic regions that are more stable than the 19q arms, both in low-and high-grade gliomas.…”

Section: Introductionmentioning

confidence: 99%

LOH 19q indicates shorter disease progression-free interval in low-grade oligodendrogliomas with EMP3 methylation

et al. 2012

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Abstract. We previously described a cohort of grade II oligodendroglioma (OII) patients, in whom the loss of heterozygosity (LOH) 19q was present in the subgroup at a higher risk of relapse. In this study, we evaluated the CpG methylation of the putative tumor suppressor epithelial membrane protein 3 (EMP3, 19q13.3) gene promoter in the same OII cohort, to investigate whether a correlation could be found between EMP3 cytogenetic and epigenetic loss and higher risk of relapse. Twenty-three tumor samples from OII patients were collected over a period of 10 years. Seventeen glioblastoma (GBM) samples (2 of which were relapses) were collected from 15 patients. The EMP3, O 6 -methylguanine methyltransferase (MGMT) and cyclooxygenase 2 (COX2) promoter methylation, evaluated by methylation-specific PCR, and the isocitrate dehydrogenase 1 (IDH1) mutation, identified by sequencing, were compared between the OII and GBM histotypes. The EMP3 promoter methylation was correlated with the analysis of LOH 19q, performed by microsatellite amplification, in OII patients. Disease progression-free interval was evaluated in the OII patients with the EMP3 methylation with either LOH 19q or conserved chromosome 19 arms. The EMP3 and MGMT promoter methylation was more frequent in OII than in GBM patients, and the IDH1 mutation was absent in GBM. The COX2 promoter was unmethylated in both histotypes. Both LOH +/-19q OII patients showed EMP3 hypermethylation. Concomitant LOH 19q and EMP3 gene promoter methylation was observed in the OII patients at a higher risk of relapse. Our results suggest that a total (cytogenetic and epigenetic) functional loss of both EMP3 alleles accounts for the reduced disease progression-free interval in OII patients. Although the small sample size limits the strength of this study, our results support testing this hypothesis in larger cohorts of patients, considering the methylation of the EMP3 gene promoter together with LOH 19q as an indication for treatment with adjuvant therapy ab initio in order to improve the overall survival of OII patients.

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Correlations Between O6-Methylguanine DNA Methyltransferase Promoter Methylation Status, 1p and 19q Deletions, and Response to Temozolomide in Anaplastic and Recurrent Oligodendroglioma: A Prospective GICNO Study

Cited by 169 publications

References 21 publications

IDH1 and IDH2 Mutations Are Prognostic but not Predictive for Outcome in Anaplastic Oligodendroglial Tumors: A Report of the European Organization for Research and Treatment of Cancer Brain Tumor Group

IDH1 and IDH2 Mutations Are Prognostic but not Predictive for Outcome in Anaplastic Oligodendroglial Tumors: A Report of the European Organization for Research and Treatment of Cancer Brain Tumor Group

The hypermethylation of the O⁶‐methylguanine‐DNA methyltransferase gene promoter in gliomas—correlation with array comparative genome hybridization results and IDH1 mutation

LOH 19q indicates shorter disease progression-free interval in low-grade oligodendrogliomas with EMP3 methylation

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Correlations Between O6-Methylguanine DNA Methyltransferase Promoter Methylation Status, 1p and 19q Deletions, and Response to Temozolomide in Anaplastic and Recurrent Oligodendroglioma: A Prospective GICNO Study

Cited by 169 publications

References 21 publications

IDH1 and IDH2 Mutations Are Prognostic but not Predictive for Outcome in Anaplastic Oligodendroglial Tumors: A Report of the European Organization for Research and Treatment of Cancer Brain Tumor Group

IDH1 and IDH2 Mutations Are Prognostic but not Predictive for Outcome in Anaplastic Oligodendroglial Tumors: A Report of the European Organization for Research and Treatment of Cancer Brain Tumor Group

The hypermethylation of the O6‐methylguanine‐DNA methyltransferase gene promoter in gliomas—correlation with array comparative genome hybridization results and IDH1 mutation

LOH 19q indicates shorter disease progression-free interval in low-grade oligodendrogliomas with EMP3 methylation

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The hypermethylation of the O⁶‐methylguanine‐DNA methyltransferase gene promoter in gliomas—correlation with array comparative genome hybridization results and IDH1 mutation