Loss of expression of DNA repair enzymes MGMT, hMLH1, and hMSH2 during tumor progression in gastric cancer.
BACKGROUND
Disorders of the DNA repair system that protects against alkylating mutagens are known to play an important role in carcinogenesis.


METHODS
We investigated the expression of the DNA repair enzyme that protects against alkylating mutagens, O(6)-methylguanine DNA methyltransferase (MGMT), and the mismatch repair (MMR) enzymes, hMLH1 and hMSH2, in 135 gastric cancer specimens by immunohistochemical means.


RESULTS
The immunoreactivity of MGMT and MMR proteins correlated significantly with several clinicopathologic factors. The survival curve in 116 patients showed that a loss of MGMT or hMLH1, but not of hMSH2, correlated with a poor prognosis. Combined evaluation of MGMT and hMLH1 revealed that the survival of patients with negative status for both MGMT and hMLH1 was shortest. However, this significant association between patient survival and MGMT or hMLH1 expression disappeared when early and advanced cancers were separately analyzed, indicating that synchronous losses of MGMT and hMLH1 increase during tumor progression and stage. Further evaluation according to histologic type revealed that loss of MGMT, hMLH1, and hMSH2 expression significantly differed between early and advanced cancer in differentiated-type cancers. In contrast, in undifferentiated-type cancer, loss of MGMT and MMR expression was frequently found even in intramucosal (m) cancer, and no significant difference was found in loss of hMLH1 and hMSH2 between early and advanced cancer.


CONCLUSIONS
These findings demonstrate that the reduced expression of MGMT, hMLH1, and hMSH2 in differentiated-type cancer may play an important role during tumor progression between the early and advanced stage. On the other hand, in undifferentiated-type cancer, loss of MGMT and the MMR proteins appears to be an important event at carcinogenesis or at an earlier step of tumor progression.
Kitajima
Yoshihiko
Y
Department of Surgery, Saga Medical School, 5-1-1 Nabeshima, Saga 849-0937, Japan.
Miyazaki
Kohji
K
Matsukura
Shiroh
S
Tanaka
Masayuki
M
Sekiguchi
Mutsuo
M
D048868:Adaptor Proteins, Signal Transducing; D000231:Adenocarcinoma, Papillary / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000368:Aged; D020137:Base Pair Mismatch / Q000502:physiology*; D018279:Carcinoma, Signet Ring Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002352:Carrier Proteins; D045643:DNA Repair Enzymes / Q000096:biosynthesis*; D004268:DNA-Binding Proteins; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D007564:Japan; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D009367:Neoplasm Staging; D009687:Nuclear Proteins; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000096:biosynthesis*; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D013223:Statistics as Topic; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D013997:Time Factors
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; D045643:DNA Repair Enzymes