O6-methylguanine DNA methyltransferase status determined by promoter methylation and immunohistochemistry in gliosarcoma and their clinical implications

Abstract

O(6)-methylguanine-DNA methyltransferase (MGMT) is known as a DNA repair protein, and loss of function in MGMT is related to an increase in survival in patients with malignant gliomas treated with alkylating agents. In the present study, we determined the status of MGMT using methylation-specific polymerase chain reaction (PCR) and immunohistochemistry on paraffin-embedded specimens in 12 human gliosarcomas, and these results were then related to overall survival (OS) and response to alkylating agents. The MGMT promoter was methylated in six patients. Immunostaining of MGMT was positive in 58.3% of patients. MGMT methylation status was correlated with immunostaining results in five patients (41.7%). The median OS and progression-free survival (PFS) of the whole population were 13.4 months [95% confidence interval (CI), 12.3-14.5 months] and 8.3 months (95% CI, 7.4-9.2 months), respectively. In patients with methylated MGMT promoter, median OS was 15.0 months, compared with 11.3 months in the unmethylated group. Median PFS of gliosarcoma patients was 10.3 months for the methylated group, whereas it was 7.3 months for the unmethylated group. On multivariate analysis, patients with methylated MGMT promoter had better prognosis than patients with unmethylated MGMT promoter with respect to OS and PFS (P = 0.045 and 0.034, respectively). However, there was no statistical significance between MGMT protein expression and survival. The results show that a significant fraction of gliosarcomas have MGMT promoter methylation and protein expression, and suggest that patient survival is associated with MGMT methylation status.

A study of clinico‐pathological parameters and O6 – methylguanine DNA methyltransferase (MGMT) promoter methylation status in the prognostication of gliosarcoma

“…(M, PCR product amplified by methylated-specific primers; UM, PCR product amplified by non-methylated-specific primers; L, ladder; SW48, methylated control DNA; PBL, non-methylated control DNA). Gels marked 1 to 19 represent the following cases in order: 20,17,7,8,6,2,3,21,15,22,12,4,10,9,18,11,19 and 16 (see Table 1). Cases 5, 13 and 14 did not have sufficient DNA and have not been shown.…”

“…[3][4][5] It is a well known epigenetic phenomenon associated with better treatment response and prognosis in GBMs, 4,6,7 although its importance in gliosarcoma has been analyzed in only one study to date. 8 The significance of the proportion of the glial and mesenchymal elements in gliosarcoma is another area which has been the subject of recent studies. Salvati et al 9 proposed two pathological subtypes of gliosarcomas: predominantly gliomatous (PG) and predominantly sarcomatous (PS), with better survival in the PS group probably due its superficial and well circumscribed "meningioma-like" nature allowing for better resection.…”

Aberrant Methylation of Different DNA Repair Genes Demonstrates Distinct Prognostic Value for Esophageal Cancer

“…The methylation of MGMT gene promoter regulates its protein expression; therefore, it can be considered as a potential molecular marker to predict the drug resistance of tumors to alkylating agents [23,24,[29][30][31][32][33][34][35][36]. The KaplanMeier survival analysis of the follow-up clinical information of the patients and the corresponding MGMT gene methylation status showed that the survival periods of patients with MGMT methylation were significantly longer than those without MGMT methylation.…”

“…The methylation of hMLH1 and hMSH2 promoters could cause abnormal gene expression, but whether MMR proteins function in drug resistance to chemotherapy is still a matter of debate. However, O 6 -methylguanine-DNA methyltransferase (MGMT), a DNA repair protein, plays a clear role in drug resistance and may affect the prognosis of the patients [23,24]. The expression of MGMT is closely correlated to the methylation of the MGMT gene.…”

Pediatric gliosarcoma treated with adjuvant radiotherapy and temozolomide

“…Small sample size could have possibly masked the difference. Similarly, Kang et al [10] reported MGMT methylation rate of 50 %. Recently, we reported 50 % MGMT methylation in pediatric GBM patients [6].…”