MGMT methylation: A marker of response to temozolomide in low‐grade gliomas

Everhard, Sibille; Kaloshi, Gentian; Crinière, Emmanuelle; Benouaich‐Amiel, Alexandra; Lejeune, Julie; Marie, Yannick; Sanson, Marc; Kujas, M.; Mokhtari, Karima; Hoang-Xuân, Khê; Delattre, Jean‐Yves; Thillet, Joëlle

doi:10.1002/ana.21044

Cited by 196 publications

(121 citation statements)

References 16 publications

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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: 62%

“…The methylated and thus inactivated MGMT gene promoter region indicates a better prognosis in glioblastoma patients treated with the alkylating agent temozolomide (Hegi et al, 2004(Hegi et al, , 2005. A prognostic value of MGMT methylation has also been found in anaplastic oligodendroglial tumors and low-grade gliomas (Everhard et al, 2006;van den Bent et al, 2009). Even if no consensus exists as to the best method for assessing the MGMT methylation status, pyrosequencing technology has proven to be a promising tool (Mikeska et al, 2007;Karayan-Tapon et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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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

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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Section: Discussioncontrasting

confidence: 62%

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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“…63 One might speculate that the differences in outcome attributed to the MGMT status were, in fact, due to the alkylating agent therapy that was present in the latter study. Both MGMT promoter methylation 64 and low MGMT protein levels 23 were reported to predict a favorable response to temozolomide in low-grade oligodendrogliomas. In addition, a correlation exists between MGMT promoter methylation and the 1p19q co-deletion and mutations of the IDH1 gene in these tumors, 57,59 as well as in anaplastic gliomas 14,59 (see above).…”

Section: Low-grade Gliomamentioning

confidence: 99%

MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

et al. 2009

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The DNA repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT) antagonizes the genotoxic effects of alkylating agents. MGMT promoter methylation is the key mechanism of MGMT gene silencing and predicts a favorable outcome in patients with glioblastoma who are exposed to alkylating agent chemotherapy. This biomarker is on the verge of entering clinical decision-making and is currently used to stratify or even select glioblastoma patients for clinical trials. In other subtypes of glioma, such as anaplastic gliomas, the relevance of MGMT promoter methylation might extend beyond the prediction of chemosensitivity, and could reflect a distinct molecular profile.Here, we review the most commonly used assays for evaluation of MGMT status, outline the prerequisites for standardized tests, and evaluate reasons for difficulties in reproducibility. We critically discuss the prognostic and predictive value of MGMT silencing, reviewing trials in which patients with different types of glioma were treated with various chemotherapy schedules, either upfront or at recurrence. Standardization of MGMT testing requires comparison of different technologies across laboratories, and prospectively validated cut-off values for prognostic or predictive effects. Moreover, future clinical trials will need to determine, for each subtype of glioma, the degree to which MGMT promoter methylation is predictive or prognostic, and whether testing should become routine clinical practice.

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“…It is widely believed that low-level expression in a wide spectrum of human tumors results from epigenetic silencing of the MGMT gene, largely because of hypermethylation of its promoter. [39][40][41] Low-level MGMT expression results in the accumulation of guanine-to-adenosine transition mutations and also furthers genomic instability. 42,43 However, it is a predictive marker of a favorable outcome in patients with temozolomide-treated glioblastomas.…”

Section: Temozolomidementioning

confidence: 99%

Treatment of pituitary neoplasms with temozolomide

Syro

Ortíz

Scheithauer

et al. 2010

Cancer

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Temozolomide, an orally administered alkylating agent, is used to treat malignant gliomas. Recent reports also have documented its efficacy in the treatment of pituitary adenomas and carcinomas. Temozolomide methylates DNA and thereby exhibits an antitumor effect. O 6 -methylguanine-DNA methyltransferase (MGMT), a DNA repair enzyme, removes alkylating adducts induced by temozolomide, counteracting its effects. The authors of this review conducted a Medline database search regarding temozolomide in the treatment of pituitary tumors. Demographic characteristics, tumor types, and therapeutic responses were noted in all patients. Data regarding MGMT immunoexpression, which was documented in some studies, were correlated with information regarding clinical and radiologic responses. To date, there have been 19 reported cases of adenohypophyseal tumors treated with temozolomide, including 13 adenomas and 6 carcinomas. Ten of those 13 adenomas responded favorably, and 2 nonresponsive tumors had highlevel MGMT immunoexpression. All 6 carcinomas responded to therapy, but data regarding MGMT expression were available for only 3 patients, and each had low MGMT expression. In 2 adenomas, morphologic studies were performed both before and after the patients received temozolomide. The responsive tumor had necrosis, hemorrhage, fibrosis, and neuronal differentiation. The nonresponsive tumor had no changes. There have been no reported complications attributable to temozolomide. The current results indicated that temozolomide is efficacious in the treatment of aggressive pituitary adenomas and pituitary carcinomas. Evidence indicated that low-level MGMT immunoexpression is correlated with a favorable response. A significant proportion of pituitary adenomas and carcinomas had low MGMT immunoexpression. Cancer 2011;117:454-62.

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MGMT methylation: A marker of response to temozolomide in low‐grade gliomas

Cited by 196 publications

References 16 publications

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

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

MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

Treatment of pituitary neoplasms with temozolomide

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MGMT methylation: A marker of response to temozolomide in low‐grade gliomas

Cited by 196 publications

References 16 publications

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

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

MGMT promoter methylation in malignant gliomas: ready for personalized medicine?

Treatment of pituitary neoplasms with temozolomide

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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

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