Correlation of MGMT promoter methylation status with gene and protein expression levels in glioblastoma

Uno, Miyuki; Oba-Shinjo, Sueli Mieko; Camargo, Anamaria A.; Moura, Ricardo P.; Aguiar, Paulo Henrique Pires de; Cabrera, Hector Navarro; Begnami, M. F. S.; Rosemberg, Sérgio; Teixeira, Manoel Jacobsen; Marie, Suely Kazue Nagahashi

doi:10.1590/s1807-59322011001000013

Cited by 84 publications

(62 citation statements)

References 37 publications

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“…Assessment of MGMT expression by immunochemistry, a cost-effective method, has also been proposed, but it did not seem to correlate well with promoter methylation (Uno et al 2011). Since then, various methylation-independent mechanisms of MGMT expression have been described, explaining this discrepancy (Lavon et al 2007, Kitange et al 2012, Kohsaka et al 2012, Kreth et al 2013.…”

Section: Introductionmentioning

confidence: 99%

MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors

Cros

Hentic

Rebours

et al. 2016

Endocrine-Related Cancer

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Temozolomide (TEM) showed encouraging results in well-differentiated pancreatic neuroendocrine tumors (WDPNETs). Low O 6 -methylguanine-DNA methyltransferase (MGMT) expression and MGMT promoter methylation within tumors correlate with a better outcome under TEM-based chemotherapy in glioblastoma. We aimed to assess whether MGMT expression and MGMT promoter methylation could help predict the efficacy of TEM-based chemotherapy in patients with WDPNET. Consecutive patients with progressive WDPNET and/or liver involvement over 50% who received TEM between 2006 and 2012 were retrospectively studied. Tumor response was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 guidelines. Nuclear expression of MGMT was assessed by immunochemistry (H-score, 0-300) and MGMT promoter methylation by pyrosequencing. Forty-three patients (21 men, 58 years (27-84)) with grade 1 WDPNET (n = 6) or 2 (n = 36) were analyzed. Objective response, stable disease, and progression rates were seen in 17 patients (39.5%), 18 patients (41.9%), and 8 patients (18.6%), respectively. Low MGMT expression (≤50) was associated with radiological objective response (P = 0.04) and better progression-free survival (PFS) (HR = 0.35 (0.15-0.81), P = 0.01). Disease control rate at 18 months of treatment remained satisfying with an MGMT score up to 100 (74%) but dropped with a higher expression. High MGMT promoter methylation was associated with a low MGMT expression and longer PFS (HR = 0.37 (0.29-1.08), P = 0.05). Low MGMT score (≤50) appears to predict an objective tumor response, whereas an intermediate MGMT score (50-100) seems to be associated with prolonged stable disease.

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Section: Introductionmentioning

confidence: 99%

MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors

Cros

Hentic

Rebours

et al. 2016

Endocrine-Related Cancer

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“…The above changes could cause incomplete downregulation of MGMT protein expression. In addition to methylation of CpG islands in the promoter region, which is the most significant mechanism of MGMT regulation that suppresses MGMT transcription [26,27], other mechanisms, such as MGMT genetic changes [28,29], histone modifications [30,31], p53 derangement [32,33] and post-transcriptional regulation [34,35] could also lead to MGMT silencing. Absence of MGMT protein expression (IHC-) in 15.8 % of our unmethylated (MSP-) GBM cases (Table 3) would be the result of other MGMT silencing mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Prognosis of glioblastoma with faint MGMT methylation-specific PCR product

Hsu

Lin

et al. 2015

J Neurooncol

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Methylation-specific polymerase chain reaction (MSP) for the promoter methylation status of O(6)-methylguanine-DNA-methyltranferase (MGMT) gene theoretically provides a positive or negative result. However, the faint MSP product is difficult to interpret. The aim of this study was to evaluate the significance of faint MSP product in glioblastoma (GBM). Critical concentrations of methylated control DNA, i.e., 100, 1, 0.5 and 0 % were run parallel with 116 newly diagnosed GBMs in order to standardize the interpretation and to distinguish positive (+), equivocal (±), and negative (-; unmethylated) results. Cases with the faint MSP product and its intensity between those of 1 and 0.5 % DNA controls were considered equivocal (±). MGMT methylation quantifications were also determined by quantitative real-time MSP (qMSP) and pyrosequencing (PSQ), and protein expression was detected by immunohistochemistry. There were significant correlations between MSP and all the aforementioned studies. The concordance rates between the MSP+ and qMSP+ cases, as well as the MSP- and qMSP- cases were 100 %, and the MSP± cases comprised 76.5 % of qMSP+ cases and 23.5 % of qMSP- cases. PSQ study showed that heterogeneous methylation was more frequently encountered in the MSP± cases. Multivariate analyses disclosed that although the overall survival of the MSP± cases was indistinct from that of the MSP+ cases, its progression free survival was significantly worse and was indistinct from that of the MSP- cases. In conclusion, GBMs with faint MGMT MSP products should be distinguished from MSP+ cases as their behaviors were different.

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“…With respect to the effects of MGMT on glioma, Uno et al (2011) found that the positive rate of MGMT methylation was 43.1%, and that methylation was related to low gene expression. Esteller et al (2000) indicated that 40% of patients experienced MGMT promoter methylation, and higher levels of methylation were associated with a worse prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…These results support the conclusion that MGMT methylation plays an important role in the occurrence and development of glioma. MGMT promoter methylation results in gene silencing (Hegi et al, 2005;Uno et al, 2011), and is therefore considered a predictive factor for evaluating the effect of treatment by TMZ in glioblastoma multiforme (GBM) patients (Hegi et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

Impact of MTHFR polymorphisms on methylation of MGMT in glioma patients from Northeast China with different folate levels

Liu¹,

Jiang²,

Song³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. Hypomethylation of the O6-methylguanine-DNAmethyltransferase (MGMT) promoter in glioma cells has been associated with temozolomide resistance. S-adenosylmethionine (SAM), which is produced during folate metabolism, is the main source of methyl groups during DNA methylation. As a key enzyme during folate metabolism, polymorphisms of 5,10-methylenetetrahydrofolate reductase (MTHFR) may regulate folate end-products. We investigated the effect of typical polymorphisms of MTHFR (C677T and A1298C) on MGMT methylation based on different serum folate levels in patients with glioma from Northeast China. A total of 275 patients with glioma and 329 without malignant MTHFR polymorphisms and MGMT methylation tumors were tested. Serum folate concentration was assayed by using the electrochemiluminescence immunoassay. MTHFR polymorphisms were detected by Taqman-Fluorescence quantitative polymerase chain reaction (PCR). Methylation-specific PCR was used to assess MGMT methylation. The constituent ratio of glioma patients below the serum folate biological reference value was significantly higher than that of the control population (P < 0.001). In patients with oligodendroglioma and glioblastoma, heterozygotes for the A1298C mutation were found in higher frequency than homozygotes or wild types (oligodendroglioma, P < 0.001; glioblastoma, P < 0.01). When grouped by the median or biological reference value of serum folate, only homozygotes for C677T with low levels of folate were significantly associated with decreased methylation of MGMT (median, P < 0.001; biological reference value, P = 0.036). These data suggest that, in combination with a negative folate balance in glioma patients, T/T genotypes in MTHFR C677T may be associated with MGMT demethylation.

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Correlation of MGMT promoter methylation status with gene and protein expression levels in glioblastoma

Cited by 84 publications

References 37 publications

MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors

MGMT expression predicts response to temozolomide in pancreatic neuroendocrine tumors

Prognosis of glioblastoma with faint MGMT methylation-specific PCR product

Impact of MTHFR polymorphisms on methylation of MGMT in glioma patients from Northeast China with different folate levels

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