O6-methylguanine DNA-methyltransferase methylation status can change between first surgery for newly diagnosed glioblastoma and second surgery for recurrence: clinical implications

Abstract

O(6)-methylguanine DNA-methyltransferase (MGMT) promoter methylation status is a prognostic factor in newly diagnosed glioblastoma patients. However, it is not yet clear whether, and if so how, MGMT methylation status may change. Moreover, it is unknown whether the prognostic role of this epigenetic feature is retained during the disease course. A retrospective analysis was made using a database of 614 glioblastoma patients treated prospectively from January 2000 to August 2008. We evaluated only patients who met the following inclusion criteria: age > or = 18 years; performance status 0-2; histological diagnosis of glioblastoma at both first and second surgery for recurrence; postoperative treatment consisting of: (i) radiotherapy (RT) followed by adjuvant temozolomide (TMZ) until 2005 and (ii) TMZ concurrent with and adjuvant to RT after 2005; a time interval > or = 3 months between first and second surgery. MGMT status was evaluated at first and second surgery in all 44 patients (M:F 32:12, median age: 49 years, range: 27-67 years). In 38 patients (86.4%), MGMT promoter status was assessable at both first and second surgery. MGMT methylation status, changed in 14 patients (37%) of second surgery samples and more frequently in methylated than in unmethylated patients (61.5% vs 24%, P = .03). The median survival was significantly influenced only by MGMT methylation status determined at first surgery (P = .04). Significant changes in MGMT methylation status during the course of GBM occur more frequently in MGMT methylated than unmethylated cases. MGMT methylation status determined at first surgery appears to be of prognostic value; however, it is not predictive of outcome following second surgery.

Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas

“…23 The results reported here are based on 80 patients with de novo glioblastomas and available tissue specimens from both primary and Early Detection and Diagnosis recurrent tumors. In contrast to the study by Brandes et al, 23 our data indicate that the MGMT methylation status of the primary tumor is retained in the respective recurrence in the vast majority of patients irrespective of treatment modality (radiotherapy or combined radiotherapy and chemotherapy). Only 4 of the 80 patients (6.25%) can be considered as ''true changers'' in whom loss or decrease of MGMT promoter methylation at tumor recurrence could not be explained by a low tumor cell content of the respective tissue samples.…”

“…In the absence of data indicating a differential response to rechallenge with TMZ or other alkylating drugs in these patients as opposed to the rare patients who lost MGMT methylation upon tumor recurrence, repeated MGMT methylation testing is of limited value. The data of Brandes et al 23 would support this conclusion as the assessment of MGMT promoter methylation performed on recurrent tumor samples was not predictive of outcome following second surgery in their patient series. Our data, however, show that MGMT promoter methylation correlated with clinical outcome (PRS and OS) and retained predictive value even for PRS under therapy, an effect that has not been reported so far.…”

Resveratrol reverses temozolomide resistance by downregulation of MGMT in T98G glioblastoma cells by the NF-κB-dependent pathway

“…In addition, NF-κB may also induce re-expression of MGMT and thus results in acquired TMZ-resistance of glioblastoma cells. This concept could be supported by the fact that the expression of MGMT increased in 83.3% patients who have methylated promoter and negative MGMT expression before TMZ-treatment (21). However, whether activated NF-κB strengthens MGMT expression by directly de-methylating its promoter is not evidenced although a previous study indicates that under the chemotherapeutic stress, MGMT promoter experiences de-methylation in 27.8-61.5% of glioblastoma patients (22).…”

Comparative assessment of 5 methods (methylation‐specific polymerase chain reaction, methylight, pyrosequencing, methylation‐sensitive high‐resolution melting, and immunohistochemistry) to analyze O6‐methylguanine‐DNA‐methyltranferase in a series of 100 glioblastoma patients

“…Most studies reporting a link between MGMT promoter methylation and survival in GBM patients have used methylation-specific polymerase chain reaction (MS-PCR). 6,[7][8][9][10] One of the major problems of this type of technique is the subjectivity linked to eye reading of the gel and the lack of automation. This led to the development of alternative techniques including real-time quantitative MS-PCR, MethyLight, pyrosequencing, methylation-sensitive high-resolution melting, COBRA (COmbined Bisulfite Restriction Analysis), and multiplex ligation-dependent probe amplification (MLPA).…”