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Deficient Expression of O⁶-Methylguanine-DNA Methyltransferase Combined With Mismatch-Repair Proteins hMLH1 and hMSH2 Is Related to Poor Prognosis in Human Biliary Tract Carcinoma

From the Department of Surgery (NK, KM, SM, HY, YK, KK), Saga Medical School, Saga, Japan; Department of Biochemistry (MF, YN), Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; and Department of Biology (MS), Fukuoka Dental College, Fukuoka, Japan.

Correspondence: Address correspondence and reprint requests to: Kohji Miyazaki, MD, PhD, Department of Surgery, Saga Medical School, Nabeshima 5-1-1, Saga, Japan 849-8501; Fax: 81-952-34-2019; E-mail: iyazak2@ post.saga-med.ac.jp.

Background: O⁶-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that transfers methyl groups from O⁶-methylguanine to itself. Alkylation of DNA at the O⁶ position of guanine is an important step in the induction of mutations in the organism by alkylating agents. The O⁶-methyl G:T mismatch is recognized by the mismatch-repair (MMR) pathway. The biliary duct is highly exposed to alkylating agents because of its anatomical location.

Methods: We examined 39 surgically resected gallbladder carcinomas and 35 extrahepatic bile duct carcinomas and evaluated the expression of MGMT and MMR protein (hMLH1 and hMSH2) by immunohistochemical staining.

Results: MGMT-negative staining was detected in 59.0% of gallbladder carcinoma specimens and 60.0% of extrahepatic bile duct carcinoma specimens. In gallbladder carcinoma, hMLH1- and hMSH2-negative staining was observed in 51.3% and 59.0%, respectively, whereas in extrahepatic bile duct carcinoma, the respective values were 57.1% and 65.7%. MGMT-negative staining correlated with hepatic invasion in gallbladder carcinoma and with poor prognosis in both types of tumor. Furthermore, a combined MGMT and MMR status was shown to be a more significant prognostic biomarker in both tumor types.

Conclusions: Combined MGMT and MMR is a possible prognostic marker that probably reflects an accumulation of genetic mutations.

Key Words: Biliary tract carcinoma • MGMT • hMLH1 • hMSH2

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