O-methylguanine-DNA methyltransferase (MGMT) mRNA expression predicts outcome in malignant glioma independent of MGMT promoter methylation

Background: We analyzed prospectively whether MGMT
(O(6)-methylguanine-DNA methyltransferase) mRNA expression gains
prognostic/predictive impact independent of MGMT promoter
methylation in malignant glioma patients undergoing radiotherapy
with concomitant and adjuvant temozolomide or temozolomide alone.
As DNA-methyltransferases (DNMTs) are the enzymes responsible for
setting up and maintaining DNA methylation patterns in eukaryotic
cells, we analyzed further, whether MGMT promoter methylation is
associated with upregulation of DNMT expression. 12 Hide Figures
Abstract Introduction Methods Results Discussion Acknowledgments
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Abstract Background We analyzed prospectively whether MGMT
(O6-methylguanine-DNA methyltransferase) mRNA expression gains
prognostic/predictive impact independent of MGMT promoter
methylation in malignant glioma patients undergoing radiotherapy
with concomitant and adjuvant temozolomide or temozolomide alone.
As DNA-methyltransferases (DNMTs) are the enzymes responsible for
setting up and maintaining DNA methylation patterns in eukaryotic
cells, we analyzed further, whether MGMT promoter methylation is
associated with upregulation of DNMT expression.
Methodology/Principal Findings: Adult patients with a
histologically proven malignant astrocytoma (glioblastoma: N = 53,
anaplastic astrocytoma: N = 10) were included. MGMT promoter
methylation was determined by methylation-specific PCR (MSP) and
sequencing analysis. Expression of MGMT and DNMTs mRNA were
analysed by real-time qPCR. Prognostic factors were obtained from
proportional hazards models. Correlation between MGMT mRNA
expression and MGMT methylation status was validated using data
from the Cancer Genome Atlas (TCGA) database (N = 229
glioblastomas). Low MGMT mRNA expression was strongly predictive
for prolonged time to progression, treatment response, and length
of survival in univariate and multivariate models (p