Prognostic Significance and Clinicopathological Correlations of Epigenetic MGMT Gene Silencing in High Grade Diffuse Gliomas.

Abstract

Glioblastoma is the most aggressive and commonest primary malignant brain tumour. Current standard of care includes surgery, radiation, and alkylating agent chemotherapy. Despite multimodal treatment, the survival of glioblastoma patients is dismal. Loss of O6-methylguanine-DNA-methyltransferase(MGMT) protein expression due to promoter methylation reduces glioma cell DNA repair activity and resistance to alkylating agents. Thus, in world health organization (WHO) grade 4 diffuse glioma patients treated with an alkylating agent, methylated MGMT promoter is currently being considered a clinically relevant prognostic as well as predictive biomarker. Our aim was to assess the frequency of MGMT promoter methylation in WHO grade 4 diffuse glioma patients and study their prognostic role and clinicopathological correlations. A two-year prospective cohort research was conducted on 89 WHO grade 4 diffuse glioma patients. The clinical and demographic data were retrieved from our hospital information system. MGMT methylation was assessed using methylation specific polymerase chain reaction. Data was analysed using SPSS-24 software. We studied 89 cases of WHO grade 4 diffuse glioma, of which 38.2% showed methylation of MGMT promoter. There was no significant difference in age, sex, location of tumor and clinical presentation between the methylated and unmethylated groups. A statistically significant association of methylated MGMT promoter was observed with isocitrate dehydrogenase-1 (IDH1) protein expression (p = 0.050) and alpha-thalassemia/mental retardation syndrome X-linked (ATRX) loss (p = 0.003). No significant association was noted with p53 overexpression (p = 0.492) and Ki-67 index (p = 0.698). The median overall survival in these patients receiving standard radiotherapy and concomitant temozolomide chemotherapy showed a trend towards better survival in group with methylated MGMT promoter (p < 0.001). Our study suggests that methylation of MGMT promoter is more frequent in the subset of grade 4 diffuse gliomas that significantly exhibit IDH1 immunopositivity and loss of ATRX expression. Also, patients who receive radiation therapy and simultaneous temozolomide chemotherapy have a considerably better prognosis and treatment outcome, if the promoter region of MGMT is methylated.