The Impact of MGMT Promoter Methylation and Temozolomide Treatment in Serbian Patients with Primary Glioblastoma.

Nikola Jovanović,Tatjana Mitrović,Aleksandar Kostić,Nataša Vidović,Jelena Vitorović,Slaviša Stamenković,Tatjana Jevtović-Stoimenov,Svetlana Tošić,Vladimir J Cvetković,Dušica Pavlović,Miljan Krstić,Vesna Nikolov

doi:10.3390/medicina55020034

Abstract

Background and objective: Despite recent advances in treatment, glioblastoma (GBM) remains the most lethal and aggressive brain tumor. A continuous search for a reliable molecular marker establishes the methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter as a key prognostic factor in primary glioblastoma. The aim of our study was to screen Serbian patients with primary glioblastoma for an MGMT promoter hypermethylation and to evaluate its associations with overall survival (OS) and sensitivity to temozolomide (TMZ) treatment. Materials and methods: A cohort of 30 Serbian primary glioblastoma patients treated with radiation therapy and chemotherapy were analyzed for MGMT promoter methylation and correlated with clinical data. Results: MGMT methylation status was determined in 25 out of 30 primary glioblastomas by methylation-specific PCR (MSP). MGMT promoter hypermethylation was detected in 12 out of 25 patients (48%). The level of MGMT promoter methylation did not correlate with patients’ gender (p = 0.409), age (p = 0.536), and OS (p = 0.394). Treatment with TMZ significantly prolonged the median survival of a patient (from 5 to 15 months; p < 0.001). Conclusions: Due to a small cohort of primary GBM patients, our study is not sufficient for definitive conclusions regarding the prognostic value of MGMT methylation for the Serbian population. Our preliminary data suggest a lack of association between MGMT promoter methylation and overall survival and a significant correlation of TMZ treatment with overall survival. Further population-based studies are needed to assess the prognostic value of the MGMT promoter methylation status for patients with primary glioblastoma.

Highlights

Glioblastoma (GBM)—World Health Organization (WHO) grade IV diffuse glioma—represents the highly invasive and infiltrative type of primary brain tumor associated with poor prognosis and a5.6% five-year survival rate [1,2,3]
Comprehensive genomic characterization studies revealed an underlying complex network of different molecular aberrations which provoke GBM development through changes in major signaling pathways [5,6]. These studies contributed toward defining the methylation status of the O6 -methylguanine-DNA methyltransferase (MGMT) gene promoter as one of the most relevant prognostic markers in GBM patients [7,8,9,10,11]
DNA obtained from 25 patients with primary glioblastoma was subjected to methylation-specific Polymerase chain reaction (PCR) (MSP) with specific primers for methylated (M) and unmethylated (U) template detection

Summary

Introduction

Glioblastoma (GBM)—World Health Organization (WHO) grade IV diffuse glioma—represents the highly invasive and infiltrative type of primary brain tumor associated with poor prognosis and a5.6% five-year survival rate [1,2,3]. Comprehensive genomic characterization studies revealed an underlying complex network of different molecular aberrations which provoke GBM development through changes in major signaling pathways [5,6] These studies contributed toward defining the methylation status of the O6 -methylguanine-DNA methyltransferase (MGMT) gene promoter as one of the most relevant prognostic markers in GBM patients [7,8,9,10,11]. Serbian patients with primary glioblastoma for an MGMT promoter hypermethylation and to evaluate its associations with overall survival (OS) and sensitivity to temozolomide (TMZ) treatment. Further population-based studies are needed to assess the prognostic value of the MGMT promoter methylation status for patients with primary glioblastoma

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Conclusion