Promoter Hypermethylation of Mismatch Repair Gene hMLH1 Predicts the Clinical Response of Malignant Astrocytomas to Nitrosourea

• Published in: Clinical cancer research Vol. 11; no. 4; pp. 1539 - 1544
• Main Authors: FUKUSHIMA, Takao, KATAYAMA, Yoichi, WATANABE, Takao, YOSHINO, Atsuo, OGINO, Akiyoshi, OHTA, Takashi, KOMINE, Chiaki
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-02-2005
• Subjects: Adaptor Proteins, Signal Transducing; anaplastic astrocytoma; Antineoplastic agents; Astrocytoma - drug therapy; Astrocytoma - genetics; Astrocytoma - radiotherapy; Biological and medical sciences; Carrier Proteins; chemotherapy; Combined Modality Therapy; DNA Methylation; DNA, Neoplasm - genetics; DNA, Neoplasm - metabolism; glioblastoma multiforme; hMLH1; Humans; Immunohistochemistry; Medical sciences; Middle Aged; MutL Protein Homolog 1; Neoplasm Proteins - analysis; Neoplasm Proteins - genetics; Neurology; Nitrosourea Compounds - therapeutic use; Nuclear Proteins - analysis; Nuclear Proteins - genetics; Pharmacology. Drug treatments; Polymerase Chain Reaction; promoter methylation; Promoter Regions, Genetic - genetics; Survival Analysis; Treatment Outcome; Tumors of the nervous system. Phacomatoses; Malignant glioma; Nervous system diseases; Base mismatching; Nitrosoureas; Transcription promoter; Malignant astrocytoma; Central nervous system disease; Malignant tumor; Methylation; Repair gene
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-04-1625

Purpose : 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.
Experimental Design : 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.