Loss of O 6 -Methylguanine-DNA Methyltransferase Protein Expression Is a Favorable Prognostic Marker in Diffuse Large B-Cell Lymphoma

Abstract

Although aberrant promoter hypermethylation of O6-methylguanine-DNA methyltransferase (MGMT) is a favorable prognostic marker in patients with diffuse large B-cell lymphoma (DLBCL), MGMT protein expression has not been thoroughly examined. The aim of this study was to evaluate the clinical implication of MGMT protein expression and its correlation with promoter hypermethylation of the gene. We investigated MGMT protein expression by immunohistochemical analysis of 63 DLBCL patients who received cyclophosphamide as part of multidrug regimens. In addition, promoter methylation of the MGMT gene was analyzed by a methylation-specific polymerase chain reaction assay, and correlations with chemotherapeutic effect and prognosis were statistically evaluated. Immunohistochemical assay results for MGMT protein were negative in 30.2% of patients with newly diagnosed DLBCL. Immunostaining results were closely correlated with the methylation status of the promoter. Promoter DNA methylation of the gene was not detected in 34 (81.0%) of 42 tumor samples determined to be MGMT-positive DLBCL by immunostaining and was detected in 15 (88.2%) of 17 cases of MGMT-negative DLBCL. Overall survival (OS) and disease-free survival (DFS) rates were significantly higher in MGMT-negative patients than in MGMT-positive patients (5-year OS, 81.3% versus 56.6% [P = .0375]; 5-year DFS, 66.3% versus 39.9% [P = .0121]). The combined rate for complete response (CR) plus unconfirmed CR was significantly higher in MGMT-negative patients (15/19, 79.0%) than in MGMT-positive patients (25/44, 56.8%) (P = .0488). A multivariate analysis showed that absence of MGMT expression was an independent prognostic factor for OS (relative risk, 4.09; P = .0258). Lack of MGMT protein expression is associated with aberrant promoter DNA methylation and appears to be a useful marker for predicting the survival of DLBCL patients.

Determination of apoptosis, proliferation status and O6-methylguanine DNA methyltransferase methylation profiles in different immunophenotypic profiles of diffuse large B-cell lymphoma

“…Furthermore, Al-Kuraya et al determined that their frequency of GCB profile DLBCL (13%) was somewhat lower than described in previous studies. They also found a much higher rate of MGMT methylation in their patients (75.9%) as compared with previous studies [1,3,30,31,46,47]. In our study, no significant association was found between MGMT promoter methylation status and the expression levels of apoptosis-related proteins, the AI and the PI.…”

“…MGMT methylation was reported at a frequency from 36% to 52% in Western populations in previous studies [1,3,30,46,47]. Higher rates (75.9%) were found in Middle Eastern populations [38].…”

“…In human cancers, the gene encoding the DNA-repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT) is not commonly mutated or deleted. Loss of MGMT expression is mainly due to epigenetic changes, specifically methylation of the promoter region [1,30]. MGMT protects cells from the toxicity of environmental and therapeutic alkylating agents, which frequently target the O 6 position of guanine.…”

“…Inactivation of the MGMT gene via hypermethylation of its promoter region increases sensitivity of cells to the genotoxic effect of alkylating agents both in vitro and in vivo [1,3]. Recent research has focused on the relationship between MGMTmethylation status and immunophenotypic differentiation in DLBCLs [30,31].…”

CpG Methylation Analysis—Current Status of Clinical Assays and Potential Applications in Molecular Diagnostics

“…126 In addition to predicting drug response, MGMT promoter methylation is an independent predictor of better outcome in glioblastoma and diffuse large B-cell lymphoma. 124,127 …”