Article
Where lies the threshold level of MGMT promotor hypermethylation in malignant gliomas
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Published: | June 9, 2017 |
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Objective: Hypermethylation of the O6-methylguanine-DNA methyltransferase (MGMT) promotor is associated with improved treatment response and prolonged survival in glioma patients. Pyrosequencing is an approved method to determine MGMT promotor status, but still adequate threshold levels for clinical decision making need to be determined on the basis of a well-defined patient cohort.
Methods: This study included 263 newly diagnosed, previously untreated, IDH R132 wildtype malignant gliomas with the histopathological morphology of a glioblastoma multiforme WHO grade IV. IDH R132 Status was assessed with immunohistochemistry (IHC). The MGMT promoter methylation status was evaluated with methylation-specific polymerase chain reaction (MSP) and pyrosequencing (PSQ). Overall survival was correlated to percent MGMT promotor methylation.
Results: The patient population was well balanced in concerns of age, extend of surgical resection and adjuvant therapy. Patients with a KPS less than 70% were excluded from the study. The degree of MGMT promotor and GpG (GpG1-5) island methylation was independent of age and tumor localization. Statistical analysis revealed a threshold of 15-20% MGMT promotor methylation, which was associated with significant difference in survival (median survival 13 month vs. 25 month, p*=0.01, HR 1.915, 95% confidence interval 1.162 to 3.155)
Conclusion: Here we report that a reasonable threshold level of MGMT promotor methylation lies above 15-20% predicting survival benefit and therapy response. Among the investigated CpG islands CpG3 and CpG5 are the main contributors to favorable outcome. Further RCT studies need to approve the cut-off value on the basis for future treatment decisions.