Deficient expression of O(6)-methylguanine-DNA methyltransferase combined with mismatch-repair proteins hMLH1 and hMSH2 is related to poor prognosis in human biliary tract carcinoma.
BACKGROUND
O(6)-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that transfers methyl groups from O(6)-methylguanine to itself. Alkylation of DNA at the O(6) position of guanine is an important step in the induction of mutations in the organism by alkylating agents. The O(6)-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.
Kohya
Naohiko
N
Department of Surgery, Saga Medical School, Saga, Japan.
Miyazaki
Kohji
K
Matsukura
Shiroh
S
Yakushiji
Hiroyuki
H
Kitajima
Yoshihiko
Y
Kitahara
Kenji
K
Fukuhara
Masao
M
Nakabeppu
Yusaku
Y
Sekiguchi
Mutsuo
M
D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D020137:Base Pair Mismatch / Q000502:physiology; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins; D016009:Chi-Square Distribution; D004260:DNA Repair / Q000502:physiology; D004268:DNA-Binding Proteins; D005260:Female; D005706:Gallbladder Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D009687:Nuclear Proteins; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000378:metabolism*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D018709:Statistics, Nonparametric
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019853:O(6)-Methylguanine-DNA Methyltransferase; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein