Open AccessPromoter Hypermethylation of the DNA Repair Gene O 6 ‐ Methylguanine‐DNA Methyltransferase is an Independent Predictor of Shortened Progression Free Survival in Patients with Low‐grade Diffuse Astrocytomas
Author(s) -
Komine Chiaki,
Watanabe Takao,
Katayama Yoichi,
Yoshino Atsuo,
Yokoyama Takakazu,
Fukushima Takao
Publication year - 2003
Publication title -
brain pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.986
H-Index - 132
eISSN - 1750-3639
pISSN - 1015-6305
DOI - 10.1111/j.1750-3639.2003.tb00017.x
Subject(s) - o 6 methylguanine dna methyltransferase , methyltransferase , methylation , dna methylation , cancer research , univariate analysis , dna methyltransferase , temozolomide , biology , dna repair , promoter , gene , oncology , multivariate analysis , glioma , medicine , gene expression , genetics
The O 6 ‐methylguanine‐DNA methyltransferase (MGMT) plays a major role in repairing DNA damage from alkylating agents. In several human neoplasms including low‐grade diffuse astrocytomas, promoter hypermethylation of MGMT has been shown to correlate with an increased frequency of p53 mutation. In the present study, we analyzed MGMT promoter methylation by the methylation‐specific PCR in 49 newly diagnosed WHO grade II astrocytomas and evaluated its clinical usefulness. MGMT promoter methylation was found in 21 (43%) of the 49 tumors. A tight correlation existed between MGMT methylation and p53 protein accumulation (P=0.0424). The presence of MGMT methylation was significantly associated with a shorter progression free survival (PFS) on both univariate analysis (P=0.0014) and multivariate analysis (P=0.0081). It was a more powerful determinant of the PFS than age, sex, performance status, proliferative activity, or p53 expression, and was independent of the extent of surgery. In terms of the overall survival, MGMT methylation demonstrated a prognostic utility in the univariate analysis but not in the multivariate analysis. The present findings indicate that aberrant methylation of the MGMT promoter independently augurs for an unfavorable clinical course in patients with low‐grade diffuse astrocytomas. Since the presence of MGMT methylation is expected to predict an increased sensitivity to alkylating chemotherapeutic agents, earlier chemotherapy could serve to improve an unfavorable natural history in tumors with MGMT methylation.