Abstract

Although O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation status is an important marker for glioblastoma multiforme (GBM), there is considerable variability in the clinical outcome of patients with similar methylation profiles. The present study aimed to refine the prognostic and predictive value of MGMT promoter status in GBM by identifying a micro (mi)RNA risk signature. Data from The Cancer Genome Atlas was used for this study, with MGMT promoter-methylated samples randomly divided into training and internal validation sets. Data from The Chinese Glioma Genome Atlas was used for independent validation. A five miRNA-based risk signature was established for MGMT promoter-methylated GBM to distinguish cases as high- or low-risk with distinct prognoses, which was confirmed using internal and external validation sets. Importantly, the prognostic value of the signature was significant in different cohorts stratified by clinicopathologic factors and alkylating chemotherapy, and a multivariate Cox analysis found it to be an independent prognostic marker along with age and chemotherapy. Based on these three factors, we developed a quantitative model with greater accuracy for predicting the 1-year survival of patients with MGMT promoter-methylated GBM. These results indicate that the five-miRNA signature is an independent risk predictor for GBM with MGMT promoter methylation and can be used to identify patients at high risk of unfavorable outcome and resistant to alkylating chemotherapy, underscoring its potential for personalized GBM management.

Highlights

  • Glioblastoma multiforme (GBM) is the most common and deadly type of malignant tumor in the central nervous system

  • 171 miRNAs were found to be differentially expressed between non-tumor brain tissue and GBM specimens with methylguanine DNA methyltransferase (MGMT) promoter methylation

  • The majority of these (91.2%) were the same as the 166 miRNAs that were differentially expressed between non-tumor brain tissue and GBM specimens without MGMT promoter methylation (Supplementary Data 1)

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Summary

Introduction

Glioblastoma multiforme (GBM) is the most common and deadly type of malignant tumor in the central nervous system. The median survival time of GBM is 14 months even after standard treatment consisting maximal surgical resection followed by adjuvant chemotherapy and radiotherapy [1]. The survival time varies widely from < 3 months to > 3 years following diagnosis [1], underscoring the limitations of current clinicopathologic markers and grading systems in predicting patient outcome. Recent studies have identified many markers for GBM; one of the most reliable of them is the methylation status of the O(6)-methylguanine DNA methyltransferase (MGMT) gene promoter. Patients with equivalent MGMT promoter methylation status have variable prognoses and responses www.impactjournals.com/oncotarget to treatment [4], suggesting that other factors are important in determining clinical outcome

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