© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 1, 26-32,
January 2, 2002
© 2002 Oxford University Press
ARTICLE |
Hypermethylation of the DNA Repair Gene O6-Methylguanine DNA Methyltransferase and Survival of Patients With Diffuse Large B-Cell Lymphoma
Affiliations of authors: M. Esteller, Division of Cancer Biology, The Johns Hopkins Oncology Center, Baltimore, MD, and Cancer Epigenetics Laboratory, Molecular Pathology Program, Centro Nacional de Investigaciones Oncologicas, Majadahonda, Spain; G. Gaidano, D. Capello, D. Rossi, The Center for the Study and Treatment of Blood Disorders, Division of Internal Medicine, Department of Medical Sciences, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy; S. N. Goodman (Division of Biostatistics), S. B. Baylin, J. G. Herman (Division of Cancer Biology), The Johns Hopkins Oncology Center; V. Zagonel (Division of Medical Oncology B), A. Gloghini, A. Carbone (Division of Pathology), Centro di Riferimento Oncologico—Istituto Nazionale Tumori, Aviano, Italy; B. Botto, U. Vitolo, Division of Hematology, A.O. San Giovanni Battista della Città di Torino, Italy.
Correspondence to: James G. Herman, M.D., The Johns Hopkins Oncology Center, 1650 Orleans, Baltimore, MD 21231 (e-mail: hermanji{at}jhmi.edu).
Background: The gene encoding the DNA repair enzyme O6-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.
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