Implications ofMGMTpromoter methylation and its downstreamhMSH2mRNA in primary malignant glioma

Abstract

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 betweenMGMTmethylation andhMSH2mRNAexpression in HGG and their role in the prognosis was explored.MethodsStudy was performed on 54 primary-frontal lobe HGG tumors,MGMTpromoter methylation was detected by Q-MSP and Q-PCR was used to analysehMSH2m-RNA expression levels.ResultsMGMTmethylation was seen in 62%patients the mean percentage of methylation (PoM) being (17.62±17.20) %.MGMTPoM≥10% had improved Progression free survival (p=0.015) and ≥8% had better Overall survival (p=0.043), indicating its predictive significance. Over expression ofhMSH2was seen in 50% patients with a median fold change of 2.74 (p=0.021). Univariate analysis of highhMSH2expression with therapy(CT+RT) showed poor PFS (p=0.002). There was no correlation betweenMGMTmethylation andhMSH2expression.ConclusionMGMTPoM of ≥10% is a significant prognostic marker. Over expression ofhMSH2is prognostic marker for poor treatment response. Lack of/aberrant correlation betweenMGMTandhMSH2could 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.