scholarly journals Implications of MGMT promoter methylation and its downstream hMSH2 mRNA in primary malignant glioma

2019 ◽  
Author(s):  
Jeru-Manoj Manuel ◽  
K V L Narasinga Rao ◽  
G K Chetan
Keyword(s):  
Treatment Response ◽  
Prognostic Marker ◽  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Univariate Analysis ◽  
Progression Free Survival ◽  
Primary Component ◽  
Over Expression ◽  
Methylguanine Dna Methyltransferase ◽  
Protein Dimer

AbstractBackgroundHypermethylation of 06-methylguanine DNA methyltransferase (MGMT)promoter seen in high grade gliomas (HGG) leads to the accumulation of O6-meG DNA damage which mispairs with thymine, requiring recognition by mismatch repair protein dimer MutSα, whose primary component is coded by Human MutS homolog protein 2 (hMSH2). O6-meG repair necessitates the interaction/combined action of MGMT andhMSH2 to maintain genomic stability. Analysis of the correlation between MGMT methylation and hMSH2mRNAexpression in HGG and their role in the prognosis was explored.MethodsStudy was performed on 54 primary-frontal lobe HGG tumors, MGMT promoter methylation was detected by Q-MSP and Q-PCR was used to analyse hMSH2 m-RNA expression levels.ResultsMGMT methylation was seen in 62%patients the mean percentage of methylation (PoM) being (17.62±17.20) %. MGMT PoM≥10% had improved Progression free survival (p=0.015) and ≥8% had better Overall survival (p=0.043), indicating its predictive significance. Over expression of hMSH2 was seen in 50% patients with a median fold change of 2.74 (p=0.021). Univariate analysis of high hMSH2 expression with therapy(CT+RT) showed poor PFS (p=0.002). There was no correlation between MGMT methylation and hMSH2 expression.ConclusionMGMT PoM of ≥10% is a significant prognostic marker. Over expression of hMSH2 is prognostic marker for poor treatment response. Lack of/aberrant correlation between MGMT andhMSH2 could indicate impaired DNA repair of O6-meG in HGG, and this could be one of the factors responsible for both, gliomagenesis and variations in treatment response.

scholarly journals Methylation of MGMT promoter does not predict response to temozolomide in patients with glioblastoma in Donostia Hospital

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Larraitz Egaña ◽  
Jaione Auzmendi-Iriarte ◽  
Joaquin Andermatten ◽  
Jorge Villanua ◽  
Irune Ruiz ◽  
...  
Keyword(s):  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Methylation Status ◽  
Progression Free Survival ◽  
Mgmt Promoter Methylation ◽  
Mgmt Methylation ◽  
Free Survival ◽  
Methylguanine Dna Methyltransferase ◽  
Mgmt Promoter ◽  
Newly Diagnosed Glioblastoma

Abstract O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status has been considered a prognostic factor in newly diagnosed glioblastoma (GBM). In this study, we evaluated the prognostic and predictive value of MGMT promoter methylation in patients with glioblastoma in Donostia Hospital. Surprisingly, methylation of MGMT promoter did not predict response to temozolomide in patients with glioblastoma in Donostia Hospital. Specifically, overall survival (OS) and progression-free survival (PFS) did not differ significantly by MGMT methylation status in our cohort. In contrast, both were longer in patients who received treatment, received more TMZ cycles, had a better general status and perform at least a partial resection. No association was detected between methylation of MGMT promoter and molecular markers such as ATRX, IDH, p53 and Ki67. These results indicate that MGMT methylation did not influence in patient survival in our cohort.

scholarly journals Correlation of commercially available quantitative MGMT (O-6-methylguanine-DNA methyltransferase) promoter methylation scores and GBM patient survival

2018 ◽  
Vol 6 (3) ◽  
pp. 194-202
Author(s):  
Laura Dovek ◽  
Nhung T Nguyen ◽  
Byram H Ozer ◽  
Ning Li ◽  
Robert M Elashoff ◽  
...  
Keyword(s):  
Los Angeles ◽  
Promoter Methylation ◽  
Dna Methyltransferase ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Kaiser Permanente ◽  
Tissue Samples ◽  
Cox Regression Analysis ◽  
Methylguanine Dna Methyltransferase ◽  
Methylation Score

Abstract Background Between 2011 and 2016, O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation testing at University of California Los Angeles (UCLA) was performed through LabCorp, using a threshold of 2 to distinguish MGMT methylated from unmethylated tumors. In this study, we sought to determine whether the magnitude of the methylation score correlated with outcome. Methods We identified 165 newly diagnosed glioblastoma (GBM) isocitrate dehydrogenase (IDH) wild-type and temozolomide-treated upfront patients at UCLA and Kaiser Permanente Los Angeles with LabCorp-derived quantitative MGMT scores obtained on pretreatment tissue samples. Using LabCorp’s threshold, we found 102 unmethylated and 63 methylated patients. We then further substratified each group based on the magnitude of the score, and performed Kaplan-Meier and Cox regression analyses of overall survival (OS) and progression-free survival (PFS). Results We validated that the standard LabCorp threshold of 2 could separate our cohort by survival, showing longer OS and PFS for MGMT methylated patients vs unmethylated patients. Cox regression analysis confirmed that MGMT (<1) patients had worse outcome, with OS and PFS hazard ratios of 2.375 (P = .053) and 2.463 (P = .023), respectively, when compared to the MGMT (1-1.99) patients. Contrary to our expectation, when we substratified the ≥2 (methylated) group, we did not find a dose-dependent relationship between the magnitude of MGMT methylation and improved survival. Conclusions The MGMT unmethylated group contains a partially methylated group (greater than 1) that shares survival benefits similar to the methylated group. However, we did not demonstrate an association of very high methylation scores with increased survival. These findings will require validation in additional independent clinical data sets.

scholarly journals Alteration in the expression of MGMT and RUNX3 due to non-CpG promoter methylation and their correlation with different risk factors in esophageal cancer patients

Tumor Biology ◽  
2017 ◽  
Vol 39 (5) ◽  
pp. 101042831770163 ◽  
Author(s):  
Snigdha Saikia ◽  
Asad Ur Rehman ◽  
Prajjalendra Barooah ◽  
Preeti Sarmah ◽  
Mallika Bhattacharyya ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Transcription Factor ◽  
Promoter Methylation ◽  
Messenger Rna ◽  
Dna Methyltransferase ◽  
Rna Expression ◽  
Betel Nut ◽  
Methylguanine Dna Methyltransferase ◽  
Related Transcription Factor ◽  
Transcription Factor 3

Promoter methylation reflects in the inactivation of different genes like O6-methylguanine-DNA methyltransferase DNA repair gene and runt-related transcription factor 3, a known tumor suppressor gene in various cancers such as esophageal cancer. The promoter methylation was evaluated for O6-methylguanine-DNA methyltransferase and runt-related transcription factor 3 in CpG, CHH, and CHG context (where H is A, T, or C) by next-generation sequencing. The methylation status was correlated with quantitative messenger RNA expression. In addition, messenger RNA expression was correlated with different risk factors like tobacco, alcohol, betel nut consumption, and smoking habit. CpG methylation of O6-methylguanine-DNA methyltransferase promoter had a positive association in the development of esophageal cancer (p < 0.05), whereas runt-related transcription factor 3 promoter methylation showed no significant association (p = 1.0) to develop esophageal cancer. However, the non-CpG methylation, CHH, and CHG were significantly correlated with O6-methylguanine-DNA methyltransferase (p < 0.05) and runt-related transcription factor 3 (p < 0.05) promoters in the development of esophageal cancer. The number of cytosine converted to thymine (C→T) in O6-methylguanine-DNA methyltransferase promoter showed a significant correlation between cases and controls (p < 0.05), but in runt-related transcription factor 3 no such significant correlation was observed. Besides, messenger RNA expression was found to be significantly correlated with promoter hypermethylation of O6-methylguanine-DNA methyltransferase and runt-related transcription factor 3 in the context of CHG and CHH (p < 0.05). The CpG hypermethylation in O6-methylguanine-DNA methyltransferase showed positive (p < 0.05) association, whereas in runt-related transcription factor 3, it showed contrasting negative association (p = 0.23) with their messenger RNA expression. Tobacco, betel nut consumption, and smoking habits were associated with altered messenger RNA expression of O6-methylguanine-DNA methyltransferase (p < 0.05) and betel nut consumption and smoking habits were associated with runt-related transcription factor 3 (p < 0.05). There was no significant association between messenger RNA expression of O6-methylguanine-DNA methyltransferase and runt-related transcription factor 3 with alcohol consumption (p = 0.32 and p = 0.15). In conclusion, our results suggest that an aberrant messenger RNA expression may be the outcome of CpG, CHG, and CHH methylation in O6-methylguanine-DNA methyltransferase, whereas outcome of CHG and CHH methylation in runt-related transcription factor 3 promoters along with risk factors such as consumption of tobacco, betel nut, and smoking habits in esophageal cancer from Northeast India.

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