The role of direct DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT) in high grade malignant glioma

摘要

BackgroundHigh-grade [WHO, 2007- grade III-IV] gliomas areundifferentiated or anaplastic, are highly infiltrating andtermed as malignant. The overall prognosis and survivalrate is very low. Only few highly sensitive and specificbiomarkers for Glioma have been identified, but are yetto be put for routine use due to challenges in their clinicalvalidation for early disease detection, diagnosis andmonitoring to improve long-term survival of patients.The inefficacy of currently available chemotherapeuticand radio-therapeutic agents largely depends on a numberof resistance mechanisms among which DNA repairplays an important role. Hence bio-molecules involvedin DNA repair mechanisms will be promising biomarkers.Current status in the validation of DNA repairgenes include, studying the promoter methylation of theonly direct DNA repair gene O6-methylguanine-DNAmethyltransferase (MGMT). MGMT is epigeneticallyinactivated via hypermethylation of the 5′-CpG islandslocated in promoter region. It is associated with predictionof successful alkylating agent therapy with temozolomidein combination with radiotherapy and alsolonger overall survival in patients. The silenced MGMTgene possibly enhances radiation effects by inducingradiation-mediated double stranded DNA (dsDNA)breaks and suppression of dsDNA repair pathways afterradiation exposure.Materials & methodsPost surgery excised tumor samples from 20 patientsdiagnosed histopathologically with high grade gliomawere tested for MGMT promoter region methylationstatus. DNA extraction and bisulphate conversion usingsuitable commercially available kits (Qiagen) followed byMethylation specific PCR using specific methylated andunmethylated primers was carried out. Correlations areunderway with clinical profile and treatment regimen.ResultsHypermethylation of the promoter region was observedin about 60%, (12) samples. The other samples onlydemonstrated unmethylated regions.ConclusionsAssessment of promoter methylation of the MGMTgene helps in the therapeutic choice of the patients. Ithas gained importance not only as a prognostic but alsoas a predictive biomarker in molecular profiling of highgrade gliomas.