BACKGROUND: Studies in adults with malignant glioma suggest MGMT methylation as a stratification marker. Similar data for children are sparse. We investigated the impact of MGMT methylation and expression on survival of children with high-grade glioma (HGG) registered into the German HIT-GBM database receiving temozolomide (TMZ) as part of their treatment (n = 21 relapsed, n = 4 primary). PROCEDURE: Twenty-four patients were included retrospectively. Methylation specific PCR (MSP), calibrated combined bisulfite restriction analysis (COBRA), and immunohistochemistry (IHC) were applied. Survival analyses were performed by Kaplan-Meier and Cox proportional-hazards models. RESULTS: MSP demonstrated DNA methylation in 77%. Patients with a methylated MGMT promoter had a sixfold longer median EFS (P = 0.015; 5.5 months vs. 0.9 months). Considering the results of calibrated COBRA, MGMT methylation was again associated with an elevated EFS (P = 0.05; 10.2 months vs. 2.6 months) and OS (P = 0.06; 18.7 months vs. 7.2 months) only if methylation was >14%. No difference in EFS and OS at all was noted between unmethylated and tumors methylated at low level (n = 9). Twenty-two tumors were positive by IHC, 10 showed low MGMT expression (IHC score 0-4). We did not detect any difference in EFS and OS between moderate/high-expressing tumors (IHC score 6-12) and those with low or no expression (IHC score 0-4). CONCLUSION: DNA methylation, but not protein expression of MGMT was associated with an increased median EFS and OS of children with relapsed HGG. MGMT methylation status warrants prospective evaluation as a stratification marker for children with HGG. (c) 2009 Wiley-Liss, Inc.
BACKGROUND: Studies in adults with malignant glioma suggest MGMT methylation as a stratification marker. Similar data for children are sparse. We investigated the impact of MGMT methylation and expression on survival of children with high-grade glioma (HGG) registered into the German HIT-GBM database receiving temozolomide (TMZ) as part of their treatment (n = 21 relapsed, n = 4 primary). PROCEDURE: Twenty-four patients were included retrospectively. Methylation specific PCR (MSP), calibrated combined bisulfite restriction analysis (COBRA), and immunohistochemistry (IHC) were applied. Survival analyses were performed by Kaplan-Meier and Cox proportional-hazards models. RESULTS: MSP demonstrated DNA methylation in 77%. Patients with a methylated MGMT promoter had a sixfold longer median EFS (P = 0.015; 5.5 months vs. 0.9 months). Considering the results of calibrated COBRA, MGMT methylation was again associated with an elevated EFS (P = 0.05; 10.2 months vs. 2.6 months) and OS (P = 0.06; 18.7 months vs. 7.2 months) only if methylation was >14%. No difference in EFS and OS at all was noted between unmethylated and tumors methylated at low level (n = 9). Twenty-two tumors were positive by IHC, 10 showed low MGMT expression (IHC score 0-4). We did not detect any difference in EFS and OS between moderate/high-expressing tumors (IHC score 6-12) and those with low or no expression (IHC score 0-4). CONCLUSION: DNA methylation, but not protein expression of MGMT was associated with an increased median EFS and OS of children with relapsed HGG. MGMT methylation status warrants prospective evaluation as a stratification marker for children with HGG. (c) 2009 Wiley-Liss, Inc.
Authors: Rebekka Unland; Kornelius Kerl; Sabrina Schlosser; Nicole Farwick; Tanja Plagemann; Birigit Lechtape; Steven C Clifford; Jonas H Kreth; Joachim Gerss; Jörg Mühlisch; Günther H S Richter; Martin Hasselblatt; Michael C Frühwald Journal: J Neurooncol Date: 2013-11-22 Impact factor: 4.130