Abstracts
2000 Digestive Disease Week

# 2266 Deficient Expression of O6-Methylguanine- DNA Methyltransferase Correlates with the Prognosis of Hepatocellular Carcinoma.
Shiroh Matsukura, Hiroyuki Yakushiji, Akiomi Ogawa, Michito Mori, Masao Fukuhara, Akihiro Iyama, Tohoru Ishibashi, Yusaku Nakabeppu, Mutsuo Sekiguchi, Kohoji Miyazaki, Fukuoka, Japan, Saga, Japan

BACKGROUND: O6-methylguanine- DNA methyltransferase (MGMT) is an enzyme which repairs O6-methylguanine, a promutagenic DNA base damage produced by endogenous and environmental alkylating agents. Deficient or reduced MGMT expression give rise to accumulation of O6- methylguanine in cellular DNA. O6-methylguanine preferentially mispairs with thymine instead of cytosine during DNA replication, leading to a G:C to A:T transition mutation. Thus, abnormality in MGMT expression could result in activation of oncogene or inactivation of tumor suppressor gene, contributing to carcinogenesis or tumor progression in human. Recent findings from animal model studies demonstrated that deficiency in the repair of O6-methylguanine appears to be one of major determinant factors of susceptibility to carcinogenesis by alkylating agents. It is likely that abnormality in MGMT expression promotes accumulation of alterarions in such cancer- related genes. Thus, we assume that abnormality in MGMT expression may correlate with the malignant grade and prognosis of cancer patients. OBJECTIVE: We investigated whether MGMT expression correlates with clinicopathological features of hepatocellular carcinomas (HCCs) and whether the expression of the MGMT protein in tumor cells can be a prognostic marker in affected patients. MATERIALS AND METHODS: Expression of MGMT protein was evaluated immunohistochemically in 60 paraffin-embedded samples from patients with curatively resected HCCs. The Cox proportional-hazards model was used to adjust for covariates including age, sex, viral infection, liver cirrhosis, grade of tumor differentiation, and pTNM stage. RESULTS: Expression of MGMT protein was a positive predictive factor for survival of patients with HCCs. In patients with tumors expressing MGMT protein, the five-year survival rate was 95.0%, whereas in patients with MGMT-negative tumors, the survival rate was 60.8% (p<0.05). Among clinicopathological features, only the presence of hepatitis viral infection was associated with MGMT-negative HCCs. CONCLUSIONS: MGMT protein expression is a remarkable prognostic marker in patients with HCCs. This finding may be useful to predict the patients with good outcome after curative surgical treatment. Deficient MGMT expression by itself does not participate in tumor progression, however, it is suggested that deficient or reduced MGMT expression may correlate with hepatocellular carcinogenesis associated with viral infection.