Promoter hypermethylation of mismatch repair gene hMLH1 predicts the clinical response of malignant astrocytomas to nitrosourea.
OBJECTIVE
In certain types of human cancers, transcriptional inactivation of hMLH1 by promoter hypermethylation plays a causal role in the loss of mismatch repair functions that modulate cytotoxic pathways in response to DNA-damaging agents. The aim of the present study was to investigate the role of promoter methylation of the hMLH1 gene in malignant astrocytomas.


METHODS
We examined the hMLH1 promoter methylation in a homogeneous cohort of patients with 41 malignant astrocytomas treated by 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-2(2-chloroethyl)-3-nitrosourea chemotherapy in combination with radiation and interferon therapy, and assessed the correlation of such methylation with clinical outcome.


RESULTS
hMLH1 promoter methylation was found in 6 (15%) of the 41 newly diagnosed malignant astrocytomas. Hypermethylation of the hMLH1 promoter corresponded closely with a loss of immunohistochemical staining for hMLH1 protein (P = 0.0013). Patients with hMLH1-methylated tumors displayed a greater chance of responding to adjuvant therapy as compared with those with hMLH1-unmethylated tumors (P = 0.0150). The presence of hMLH1 hypermethylation was significantly associated with a longer progression-free survival on both univariate analysis (P = 0.0340) and multivariate analysis (P = 0.0161).


CONCLUSIONS
The present study identified hMLH1 methylation status as a predictor of the clinical response of malignant astrocytomas to chloroethylnitrosourea-based adjuvant therapy. The findings obtained suggest that determination of the methylation status of hMLH1 could provide a potential basis for designing rational chemotherapeutic strategies, as well as for predicting prognosis.
Fukushima
Takao
T
Department of Neurological Surgery, Nihon University School of Medicine, 30-1 Oyaguchi-kamimachi, Itabashi, Tokyo 173-8610, Japan. takao@med.nihon-u.ac.jp
Katayama
Yoichi
Y
Watanabe
Takao
T
Yoshino
Atsuo
A
Ogino
Akiyoshi
A
Ohta
Takashi
T
Komine
Chiaki
C
D048868:Adaptor Proteins, Signal Transducing; D001254:Astrocytoma / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy; D002352:Carrier Proteins; D003131:Combined Modality Therapy; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics*; D009607:Nitrosourea Compounds / Q000627:therapeutic use*; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016019:Survival Analysis; D016896:Treatment Outcome
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009607:Nitrosourea Compounds; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1