MGMT as a potential stratification marker in relapsed high-grade glioma of children: the HIT-GBM experience.

Abstract

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.

• Authors: Sabrina Schlosser, Sabine Wagner, Jörg Mühlisch, Martin Hasselblatt, Joachim Gerss, Johannes E A Wolff, Michael C Frühwald
• Journal: Pediatric blood & cancer (Pediatr Blood Cancer) Vol. 54 Issue 2 Pg. 228-37 (Feb 2010) ISSN: 1545-5017 [Electronic] United States
• PMID: 19856394 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2009 Wiley-Liss, Inc.

Chemical References

• Biomarkers, Tumor
• Tumor Suppressor Proteins
• DNA Modification Methylases
• MGMT protein, human
• DNA Repair Enzymes

Topics

• Adolescent
• Biomarkers, Tumor (genetics, metabolism)
• Child
• Child, Preschool
• DNA Methylation
• DNA Modification Methylases (genetics, metabolism)
• DNA Repair Enzymes (genetics, metabolism)
• Female
• Glioma (diagnosis, pathology)
• Humans
• Male
• Multivariate Analysis
• Prognosis
• Proportional Hazards Models
• Recurrence
• Retrospective Studies
• Survival Analysis
• Tumor Suppressor Proteins (genetics, metabolism)
• Young Adult