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MGMT as a potential stratification marker in relapsed high‐grade glioma of children: The HIT‐GBM experience
Author(s) -
Schlosser Sabrina,
Wagner Sabine,
Mühlisch Jörg,
Hasselblatt Martin,
Gerß Joachim,
Wolff Johannes E.A.,
Frühwald Michael C.
Publication year - 2010
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.22323
Subject(s) - medicine , immunohistochemistry , methylation , temozolomide , glioma , oncology , methyltransferase , dna methylation , o 6 methylguanine dna methyltransferase , proportional hazards model , pathology , cancer research , biology , gene expression , gene , genetics
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. Pediatr Blood Cancer 2010;54:228–237. © 2009 Wiley‐Liss, Inc.