title: Promoter hypermethylation of the DNA-repair gene O6-methylguanine-DNA methyltransferase and p53 mutation in diffuse large B-cell lymphoma.
abstract: The gene for the DNA-repair enzyme O6-methylguanine-DNA methyltransferase (MGMT), which is closely related with cellular sensitivity to alkylating agents, is inactivated by promoter hypermethylation in several human cancers, including malignant lymphoma. Promoter hypermethylation of the MGMT gene is a favorable prognostic factor in diffuse large B-cell lymphoma (DLBCL). Although inactivation of the MGMT gene is closely related to p53 gene mutations in several cancers, the relationship between p53 gene mutation and MGMT inactivation in malignant lymphoma has not been thoroughly examined. We studied the correlation between MGMT hypermethylation and p53 mutation in DLBCL and their impacts on patient prognosis. In a retrospective cohort study, we used a methylation-specific polymerase chain reaction technique to analyze the methylation status of the promoter region of the MGMT gene in 116 DLBCL patients who received cyclophosphamide as part of multidrug combination chemotherapies. Denaturing high-performance liquid chromatography and direct sequencing were used to search for p53 gene mutations in exons 5 through 9 in 96 of the 116 samples. Disease-free survival and overall survival were estimated by the Kaplan-Meier method. Multivariate survival analyses were performed with the Cox proportional hazards model. Forty-five (38.8%) of 116 DLBCL patients showed MGMT promoter hypermethylation. The presence of MGMT hypermethylation was associated with better overall survival (P = .036). MGMT promoter hypermethylation was a prognostic factor that was independent of established prognostic factors, such as age, disease stage, serum lactic dehydrogenase level, and the number of extranodal disease sites (hazard ratio, 2.43; 95% confidence interval, 1.28-4.61; P = .007). p53 mutations were detected in 19 (19.8%) of 96 patients and were identified as a risk factor in the complete remission rate and overall survival (P = .0040, and P = .027, respectively). A correlation between MGMT hypermethylation and p53 mutation or p53 G:C-to-A:T mutation was not observed (P = .88, and P = .31, respectively). MGMT promoter hypermethylation and p53 mutation are useful prognostic markers in DLBCL. The impact of MGMT inactivation on p53 mutation in DLBCL is unclear.
authors.affiliation: Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Hiraga
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Toshihito
authors.initials: T
authors.lastname: Ohno
authors.forename: Naoyoshi
authors.initials: N
authors.lastname: Mori
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Ohashi
authors.forename: Shouko
authors.initials: S
authors.lastname: Fukami
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Noda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ichikawa
authors.forename: Tomoki
authors.initials: T
authors.lastname: Naoe
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000235:genetics*; D015331:Cohort Studies; D019175:DNA Methylation / Q000187:drug effects; D018572:Disease-Free Survival; D005260:Female; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics*; D012189:Retrospective Studies; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D016159:Tumor Suppressor Protein p53; D019853:O(6)-Methylguanine-DNA Methyltransferase