title: Loss of O6-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.
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Toshihito
authors.initials: T
authors.lastname: Ohno
authors.forename: Junji
authors.initials: J
authors.lastname: Hiraga
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Ohashi
authors.forename: Chiho
authors.initials: C
authors.lastname: Sugisaki
authors.forename: Eika
authors.initials: E
authors.lastname: Li
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Asano
authors.forename: Tastuya
authors.initials: T
authors.lastname: Ito
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Nagai
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Yamashita
authors.forename: Naoyoshi
authors.initials: N
authors.lastname: Mori
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Tomoki
authors.initials: T
authors.lastname: Naoe
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000096:biosynthesis*; D003520:Cyclophosphamide / Q000008:administration & dosage; D019175:DNA Methylation / Q000187:drug effects; D018572:Disease-Free Survival; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000201:enzymology* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000096:biosynthesis*; D011379:Prognosis; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis / Q000187:drug effects; D015996:Survival Rate
chemical_list: D018906:Antineoplastic Agents, Alkylating; D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins; D003520:Cyclophosphamide; D019853:O(6)-Methylguanine-DNA Methyltransferase