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MGMT promoter hypermethylation is more frequent in secondary
glioblastomas and is independent from other prognostic factors
Lorena Bissola, Marica Eoli, Francesca Menghi, Bianca Pollo, Antonio
Silvani, Giovanni Broggi, Amerigo Boiardi, Gaetano Finocchiaro
Dept.
Experimental Neurology and Diagnostics. Ist. Naz. Neurol. C. Besta, Milan,
Italy, Dept. Clinical Neurology. Ist. Naz. Neurol. C. Besta, Milan, Italy, Ist.
Naz. Neurol. C. Besta, Milan, Italy, Dept. Neurosurgery. Ist. Naz. Neurol. C.
Besta, Milan, Italy. E-mail: bissola@inwind.it
O6-methylguanine-DNA methyltransferase (MGMT) is a DNA repair protein
that specifically removes mutagenic, carcinogenic and cytotoxic O6-alkylguanine
DNA adducts induced by alkylating agents like nitrosureas.
Repair of cytotoxic
DNA damage by MGMT is a potentially important factor of resistance to alkylating
agents, commonly used in the treatment of glioblastoma multiforme (GBM).
Using Methylation-Specific PCR (MSP) we investigated the inactivation of the
DNA-repair gene MGMT by promoter hypermethylation in 46 GBM obtained from
patients subsequently treated by conventional radiotherapy and BCNU.
We observed
that the MGMT gene was methylated in 16 patients (35%).
This finding was
associated with prolonged overall survival (32 versus 15 months; log-rank
p=0.004) and with a longer Progression Free Survival (PFS) (11 versus 7 months;
log-rank p=0.02).
Among these 46 GBM, secondary GBMs had prolonged overall
survival (38 versus 14 months; log-rank p=0.01) than de novo tumors,
whereas other prognostic factors were not statistically associated with ST or
PFS.
Moreover, the frequency of MGMT methylation was higher in secondary than in
primary GBMs (78% versus 22%, p=0.01), but was not associated with age, KPS and
RTOG class risk.
Other genetic markers (EGFR amplification and p53 mutations)
are under study to assess their influence on the treatment response and overall
survival of patients with GBM.
Twenty patients underwent a second surgery for
recurrence of the primary tumor and we analyzed both the first and the second
tumor DNA for MGMT promoter methylation.
Three out of six methylated gliomas
became unmethylated and three maintained their pattern, whereas 14 unmethylated
gliomas maintained the same methylation status.
Copyright © 2004 American Association for Cancer Research. All rights
reserved.
Source: http://aacr04.agora.com/planner/displayabstract.asp?presentationid=4495
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