The Association And Significance Of Inactivation Of O～6-methylguanine-DNA Methyltransferase And Promoter CpG Island Hypermethylation In Gastrointestinal Tumor

Objective To investigate the association between methylation and expression at O6-methylguanine-DNA methyltransferase in gastrointestinal carcinogenesis and progression.Methods The promoter hypermethylation of O6-methylguanine-DNA methyltransferase gene was detected in 47 gastric carcinomas, the matched normal tissues and 20 normal gastric mucosa, 27 sporadic colorectal adenomas, 62 sporadic colorectal carcinomas and 20 normal colorectal mucosa tissues by methylation-specific PCR. The expression of MGMT protein was carried out in the same samples using immunohistochemistry.Results None of the normal gastric and colorectal mucosa tissues showed methylated bands. Promoter hypermethylation was found in 19.1% (9/47) of tumors, 10.6% (5/47) of matched normal tissues, 40.7%(11/27) of colorectal adenomas and 43.5% (27/62) of carcinomas, respectively. There were 21.3% (10/47) tumors were found loss of expression and 7 cases of these (70.0%) were methylated in promoter region. The loss of MGMT expression was significantly associated with promoter CpG island hypermethylation (P0.001) ,tumor invasion(P=0.002) and pTNM stage (P=0.047) . Loss of expression was found in 22.2% (6/27) of adenomas and 45.2% (28/62) of carcinomas, respectively(P=0.041). There were 5 and 24 cases presented methylation in the 6 adenomas and 28 carcinomas losing MGMT expression, respectively.Conclusions It is suggested that during gastric carcinogenesis, the loss of O6-methylguanine-DNA methyltransferase expression frequently occurs via the hypermethylation of CpG islands of the promoter region, and this perhaps is an important pathway of gastric carcinogenesis. Promoter hypermethylation and loss of expression of MGMT gene were common events in colorectal tumorigenesis, and loss of expression of MGMT occurs more frequently in carcinoma than in adenoma in sporadic patients. Loss of MGMT expression was associated withhypermethylation of the CpG island of MGMT gene in colorectal tumor. It suggests that epigenetic inactivation of MGMT plays an important role in colorectal neoplasia.