Methylation of O6-methylguanine DNA methyltransferase and loss of heterozygosity on 19q and/or 17p are overlapping features of secondary glioblastomas with prolonged survival.
OBJECTIVE
Recent data suggest that methylation of the DNA repair gene O(6)-methylguanine DNA methyltransferase (MGMT), by increasing the chemosensitivity of glioblastoma multiforme, is significantly associated with improved prognosis. Results in contradiction with these findings, however, are present in the literature and the clinical and genetic context framing MGMT methylation is poorly characterized.


METHODS
To address these issues, we have investigated the MGMT methylation status, clinical and magnetic resonance imaging characteristics, and relevant genetic features (loss of heterozygosity on 17p and 19q, EGFR amplification, and p53 mutations) in a retrospective study on 86 patients affected by glioblastoma multiforme: 72 patients had a clinical history indicating de novo insurgence of the tumor and the remaining 14 were secondary glioblastoma multiforme.


RESULTS
MGMT methylation was detected by methylation-specific PCR in 41 of 86 cases (47.7%; Meth+). Progression-free survival and overall survival were significantly longer in Meth+ than in Meth- patients [10 versus 7 months (P=0.003, log-rank test) and 18 versus 14 months (P=0.0003, log-rank test), respectively]. Mixed-nodular enhancement at magnetic resonance imaging was significantly more frequent in Meth+ and secondary glioblastoma multiforme and ring enhancement in Meth- and primary glioblastoma multiforme (P<0.005). MGMT methylation was more present in secondary glioblastoma multiforme (P=0.006) and associated with loss of heterozygosity on 17p and/or 19q (P=0.005).


CONCLUSIONS
These observations suggest that MGMT methylation is part of a genetic signature of glioblastomas that developed from lower-grade gliomas.
Eoli
Marica
M
Unit of Clinical Neuro-Oncology, Istituto Nazionale Neurologico Besta, Milan, Italy.
Menghi
Francesca
F
Bruzzone
Maria Grazia
MG
De Simone
Tiziana
T
Valletta
Lorella
L
Pollo
Bianca
B
Bissola
Lorena
L
Silvani
Antonio
A
Bianchessi
Donatella
D
D'Incerti
Ludovico
L
Filippini
Graziella
G
Broggi
Giovanni
G
Boiardi
Amerigo
A
Finocchiaro
Gaetano
G
D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000556:secondary; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D005909:Glioblastoma / Q000175:diagnosis / Q000235:genetics* / Q000556:secondary; D005910:Glioma / Q000235:genetics / Q000473:pathology; D006801:Humans; D019656:Loss of Heterozygosity; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics*; D011379:Prognosis; D013534:Survival; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53; D019853:O(6)-Methylguanine-DNA Methyltransferase; D066246:ErbB Receptors