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


CONCLUSIONS
MGMT promoter hypermethylation appears to be a useful marker for predicting survival in patients with B-DLCL treated with multidrug regimens including cyclophosphamide.
Esteller
Manel
M
Division of Cancer Biology, The Johns Hopkins Oncology Center, Baltimore, MD 21231, USA.
Gaidano
Gianluca
G
Goodman
Steven N
SN
Zagonel
Vittorina
V
Capello
Daniela
D
Botto
Barbara
B
Rossi
Davide
D
Gloghini
Annunziata
A
Vitolo
Umberto
U
Carbone
Antonino
A
Baylin
Stephen B
SB
Herman
James G
JG
D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology*; D019175:DNA Methylation; D004260:DNA Repair; D004273:DNA, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D007150:Immunohistochemistry; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D016019:Survival Analysis
D018906:Antineoplastic Agents, Alkylating; D004273:DNA, Neoplasm; D003520:Cyclophosphamide; D019853:O(6)-Methylguanine-DNA Methyltransferase