Effect of O6‑methylguanine‑DNA methyltransferase methylation in medulloblastoma

Abstract

Abstract. Medulloblastoma is a highly malignant brain tumor that predominately affects children and requires multimodal treatment, including chemotherapy with alkylating agents. O 6 -methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that plays an important role in tumor resistance to alkylating agents. Recent studies demonstrated that MGMT promoter methylation suppresses the expression of MGMT and is associated with favorable outcomes of malignant glioma patients. However, the MGMT methylation status and its prognostic impact on medulloblastoma have not been fully elucidated to date. The objective of the present study was to investigate the association between MGMT status and clinical outcomes of pediatric medulloblastoma patients. The records of 15 patients with medulloblastoma treated at our institution were reviewed, and the methylation status of 18 CpG sites in the MGMT promoter region was determined using bisulfite sequencing analysis. A larger number of methylated CpG sites was identified in 9 patients with complete remission (median, 5 sites; range, 2-9 sites) compared with that in 6 patients with relapse (median, 2 sites, range, 1-4 sites; P=0.041). These results suggest that a higher number of methylated CpG sites in the MGMT promoter region are associated with a favorable outcome of medulloblastoma.

In search of effective therapies to overcome resistance to Temozolomide in brain tumours

“…Undetectable MGMT activity was found in as few as 10% cases, and the frequency of MGMT-deficiency was 7-fold lower in tumours recurring after alkylating agent chemotherapy. Similarly predictive (more favourable) outcomes of MGMT gene silencing are seen in peadiatric brain tumours [ 62 , 63 ] . In peadiatric, as in adult gliomas, overexpression of MGMT is strongly associated with adverse outcome in children treated with alkylator-based chemotherapy independent of other clinical prognostic factors.…”