Post-transcriptional regulation of O6-methylguanine-DNA methyltransferase MGMT in glioblastomas

Ramakrishnan, Valya; Kushwaha, Deepa; Koay, Debbie C.; Reddy, Hasini; Mao, Ying; Zhou, Lei; Ng, Kimberly; Zinn, Pascal O.; Carter, Bob S.; Chen, Clark C.

doi:10.3233/cbm-2012-0245

Cited by 35 publications

(32 citation statements)

References 27 publications

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“…We, therefore, used this technique and also found that increased promoter methylation was associated with low MGMT protein expression, although it was not perfectly correlated at the individual level. This discrepancy is not entirely surprising, as numerous methylation-independent mechanisms of MGMT expression exist, such as miRNA, histone modifications, or NF-kB/STAT3-dependent regulation (Lavon et al 2007, Ramakrishnan et al 2011, Kitange et al 2012, Kohsaka et al 2012, Zhang et al 2012, Kreth et al 2013). In addition, comparative CpG arrays and transcriptomic arrays suggested that the CpGs tested in the pyrosequencing assay are not the ones most associated with MGMT mRNA expression (Bady et al 2012).…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…This finding also signaled the limitation of MGMT promoter methylation assay, as one should not use an unmethylated result to preclude the use of TMZ in GBM patients because other MGMT silencing mechanisms could occur and patients might still benefit from this treatment. Recent studies concerning post-transcriptional regulation of MGMT have demonstrated that it could be regulated by miRNA via direct and indirect regulations [35][36][37]. Several miRNAsmiR181d, miR767-3p, miR-648 and miR-603 have been identified as significant post-transcriptional regulators of MGMT in GBMs [34,35].…”

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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“…A recent study has shown that decreased MGMT expression may be related not only to promoter methylation, but also to the methylation of other promoter-associated CpG islands [37]. Potential binding sites for several miRNAs within the 3 0 UTR of MGMT have been found [38], indicating that mechanisms such as miRNA might mediate the post-transcriptional regulation of MGMT. The identification of these regulatory mechanisms will be beneficial for MGMT-based prognostic or predictive biomarker strategies.…”

Section: Regulation Of Mgmt Expressionmentioning

confidence: 98%

Progression of O6-methylguanine-DNA methyltransferase and temozolomide resistance in cancer research

et al. 2014

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Temozolomide (TMZ) is an alkylating agent that is widely used in chemotherapy for cancer. A key mechanism of resistance to TMZ is the overexpression of O(6)-methylguanine-DNA methyltransferase (MGMT). MGMT specifically repairs the DNA O(6)-methylation damage induced by TMZ and irreversibly inactivates TMZ. Regulation of MGMT expression and research regarding the mechanism of TMZ resistance will help rationalize the clinical use of TMZ. In this review, we provide an overview of recent advances in the field, with particular emphasis on MGMT structure, function, expression regulation, and the association between MGMT and resistance to TMZ.

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Post-transcriptional regulation of O6-methylguanine-DNA methyltransferase MGMT in glioblastomas

Abstract: Our results suggest mechanisms such as miRNA mediated regulation for post-transcriptional regulation of MGMT. Identification of these mechanisms should enhance the value of MGMT based prognostic or predictive biomarker strategies.

Cited by 35 publications

References 27 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

Progression of O6-methylguanine-DNA methyltransferase and temozolomide resistance in cancer research

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