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


METHODS
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).


CONCLUSIONS
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.
Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Germany.
Sabrina
S
Schlosser
Sabine
S
Wagner
Jörg
J
Mühlisch
Martin
M
Hasselblatt
Joachim
J
Gerss
Johannes E A
JE
Wolff
Michael C
MC
Frühwald
D000293:Adolescent; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics* / Q000378:metabolism; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005910:Glioma / Q000175:diagnosis* / Q000473:pathology; D006801:Humans; D008297:Male; D015999:Multivariate Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D012008:Recurrence; D012189:Retrospective Studies; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes