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

BackgroundHypermethylation 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 MutS, 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.