Neuro-Oncology Advance Access published online on October 15, 2009
Neuro-Oncology, doi:10.1093/neuonc/nop003
O6-Methylguanine DNA methyltransferase protein expression in tumor cells predicts outcome of temozolomide therapy in glioblastoma patients
Departments of Neurosurgery (S.S.-K., C.P., D.L., J.B., J.F.); Internal Medicine (J.P.), and Institute of Pathology (R.S., S.W.); Wagner Jauregg Hospital, Wagner Jauregg Weg 15, 4020 Linz, Austria; and Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Borschkegasse 8a, 1090 Vienna, Austria (C.P., M.F., D.L., M.M., W.B.)
Corresponding Author: Sabine Spiegl-Kreinecker, PhD, Department of Neurosurgery, Wagner-Jauregg Hospital, Wagner Jauregg Weg 15, 4020 Linz, Austria (sabine.spiegl-kreinecker{at}gespag.at).
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Abstract |
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O6-Methylguanine DNA methyltransferase (MGMT) is implicated as a major predictive factor for treatment response to alkylating agents including temozolomide (TMZ) of glioblastoma multiforme (GBM) patients. However, whether the MGMT status in GBM patients should be detected at the level of promoter methylation or protein expression is still a matter of debate. Here, we compared promoter methylation (by methylation-specific polymerase chain reaction) and protein expression (by Western blot) in tumor cell explants with respect to prediction of TMZ response and survival of GBM patients (n = 71). Methylated MGMT gene promoter sequences were detected in 47 of 71 (66%) cases, whereas 37 of 71 (52%) samples were scored positive for MGMT protein expression. Although overall promoter methylation correlated significantly with protein expression (
2 test, P < .001), a small subgroup of samples did not follow this association. In the multivariate Cox regression model, a significant interaction between MGMT protein expression, but not promoter methylation, and TMZ therapy was observed (test for interaction, P = .015). In patients treated with TMZ (n = 42), MGMT protein expression predicted a significantly shorter overall survival (OS; hazard ratio [HR] for death 5.53, 95% confidence interval [CI] 1.76–17.37; P = .003), whereas in patients without TMZ therapy (n = 29), no differences in OS were observed (HR for death 1.00, 95% CI 0.45–2.20; P = .99). These data suggest that lack of MGMT protein expression is superior to promoter methylation as a predictive marker for TMZ response in GBM patients.
Keywords: O6-Methylguanine DNA methyltransferase, glioblastoma multiforme, protein expression, temozolomide
Received September 30, 2008; Accepted January 21, 2009
Material and data that appear in the article are original and have not been included in previous presentations, reports, or publications.