Hypermethylation of the DNA repair gene O(6)-methylguanine DNA methyltransferase and survival of patients with diffuse large B-cell lymphoma

J Natl Cancer Inst. 2002 Jan 2;94(1):26-32. doi: 10.1093/jnci/94.1.26.

Abstract

Background: The gene encoding the DNA repair enzyme O(6)-methylguanine DNA methyltransferase (MGMT) is transcriptionally silenced by promoter hypermethylation in several human cancers, including diffuse large B-cell lymphoma (B-DLCL). MGMT promoter hypermethylation is a favorable prognostic marker in patients with brain tumors treated with alkylating agents.

Methods: In a retrospective cohort study, we used methylation-specific polymerase chain reaction to analyze the MGMT promoter methylation status in tumor DNA of B-DLCL patients receiving cyclophosphamide as part of multidrug regimens. Molecular data were compared with patient response with the use of Student's t test. Disease-free survival and overall survival were estimated by the Kaplan-Meier method and compared with the use of the log-rank test. Multivariable survival analyses were performed with the Cox proportional hazards model. All statistical tests were two-sided.

Results: Thirty (36%) of 84 B-DLCL patients showed MGMT promoter hypermethylation in their lymphomas. The presence of MGMT methylation was associated with a statistically significant increase in overall survival (hazard ratio for time to death for nonmethylation versus methylation = 2.8; 95% confidence interval (CI) = 1.2 to 7.5; P =.01) and progression-free survival (hazard ratio for time to progression for nonmethylation versus methylation = 2.6; 95% CI = 1.3 to 5.8; P =.02). MGMT promoter hypermethylation was both independent of and stronger than established prognostic factors, such as age, disease stage, serum lactic dehydrogenase level, and performance status.

Conclusion: MGMT promoter hypermethylation appears to be a useful marker for predicting survival in patients with B-DLCL treated with multidrug regimens including cyclophosphamide.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents, Alkylating / administration & dosage
  • Antineoplastic Agents, Alkylating / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Cyclophosphamide / administration & dosage
  • Cyclophosphamide / pharmacology*
  • DNA Methylation
  • DNA Repair
  • DNA, Neoplasm
  • Gene Expression Regulation, Neoplastic*
  • Gene Silencing*
  • Humans
  • Immunohistochemistry
  • Lymphoma, B-Cell / drug therapy*
  • Lymphoma, B-Cell / genetics*
  • Lymphoma, B-Cell / metabolism
  • Lymphoma, B-Cell / mortality
  • Lymphoma, Large B-Cell, Diffuse / drug therapy*
  • Lymphoma, Large B-Cell, Diffuse / genetics*
  • Lymphoma, Large B-Cell, Diffuse / metabolism
  • Lymphoma, Large B-Cell, Diffuse / mortality
  • O(6)-Methylguanine-DNA Methyltransferase / genetics*
  • O(6)-Methylguanine-DNA Methyltransferase / metabolism
  • Polymerase Chain Reaction
  • Prognosis
  • Proportional Hazards Models
  • Retrospective Studies
  • Survival Analysis

Substances

  • Antineoplastic Agents, Alkylating
  • DNA, Neoplasm
  • Cyclophosphamide
  • O(6)-Methylguanine-DNA Methyltransferase