MGMT promoter methylation is predictive of
response to radiotherapy and prognostic in
the absence of adjuvant alkylating
chemotherapy for glioblastoma
Andreana L. Rivera†, Christopher E. Pelloski†, Mark R. Gilbert, Howard Colman,
Clarissa De La Cruz, Erik P. Sulman, B. Nebiyou Bekele, and Kenneth D. Aldape
Departments of Pathology (A.L.R., C.E.P., C.C., K.D.A.); Radiation Oncology (C.E.P., E.P.S.); Neuro-Oncology
methyltransferase (MGMT) gene has been shown to be
associated with improved outcome in glioblastoma
(GBM) and may be a predictive marker of sensitivity to
alkylating agents. However, the predictive utility of this
marker has not been rigorously tested with regard to sen-
sitivity to other therapies, namely radiation. To address
this issue, we assessed MGMT methylation status in a
cohort of patients with GBM who underwent radiation
treatment but did not receive chemotherapy as a com-
ponent of adjuvant treatment. Formalin-fixed, paraffin-
embedded tumor samples from 225 patients with newly
diagnosed GBM were analyzed via methylation-specific,
quantitative real-time polymerase chain reaction follow-
promoter methylation status. In patients who received
radiotherapy alone following resection, methylation of
the MGMT promoter correlated with an improved
response to radiotherapy. Unmethylated tumors were
twice as likely to progress during radiation treatment.
The median time interval between resection and tumor
progression of unmethylated tumors was also nearly
half that of methylated tumors. Promoter methylation
was also found to confer improved overall survival in
patients who did not receive adjuvant alkylating che-
motherapy. Multivariable analysis demonstrated that
methylation status was independent of age, Karnofsky
performance score, and extent of resection as a predictor
of time to progression and overall survival. Our data
suggest that MGMT promoter methylation appears to
be a predictive biomarker of radiation response. Since
this biomarker has also been shown to predict response
methylation represents a general, favorable prognostic
factor in GBM.
Keywords: glioblastoma, methylation, MGMT,
prognostic marker, radiotherapy
ducts from the O6position on guanine. A so-called
“suicide enzyme,” following removal of the alkyl
groups, the newly alkylated MGMT protein, is then
marked for degradation by ubiquitinization.1,2Proper
functioning of the gene is important for maintaining
cell integrity. Epigenetic silencing of the MGMT gene
by methylation of the CpG islands of the promoter
region has been shown to correlate with loss of gene
expression of the MGMT protein results in decreased
DNA repair and retention of alkyl groups, thereby
allowing alkylating agents such as carmustine (BCNU),
lomustine (CCNU), and temozolomide to have greater
efficacy in patients whose tumors exhibit hypermethyla-
tion of the MGMT promoter and reducing the MGMT
protein concentration.3–7Although MGMT protein
expression is expressed in a wide variety of tumors
including colon, head and neck, and lung cancers, infil-
trative gliomas remain one of the most intriguing and
(MGMT) gene encodes for an important DNA
repair protein which acts by removing alkyl pro-
†These authors contributed equally to this manuscript.
Corresponding Author: Christopher E. Pelloski, MD, Departments of
Pathology and Radiation-Oncology, The University of Texas M. D.
Anderson Cancer Center, 1515 Holcombe Boulevard, Unit-0097,
Houston, TX 77030 (email@example.com).
Received November 6, 2008; accepted March 23, 2009.
Neuro-Oncology 12(2):116–121, 2010.
Advance Access publication December 14, 2009
#The Author(s) 2009. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights
reserved. For permissions, please e-mail: firstname.lastname@example.org.
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Rivera et al.: MGMT promoter methylation is prognositc in GBM
†F E B R U A R Y 2 0 1 0