Inactivation of O6-methylguanine-DNA methyltransferase by promoter CpG island hypermethylation in gastric cancers

Promoter hypermethylation of CpG islands in tumour suppressor genes can lead to transcriptional inactivation. To investigate the association between methylation and expression at O-6-methylguanine-DNA methyltransferase, we performed methylation-specific PCR and immunohistochemistry in 149 gastric carcinomas. Promoter methylation was found in 14.1% of tumours and loss of expression was detected in 11.4% of tumours. To examine correlation between the O-6-methylguanine-DNA methyltransferase expression and the clinical data, we investigated O(6)methylguanine-DNA methyltransferase expression in 315 consecutive gastric carcinomas. A similar frequency of loss of O-6-methylguanine-DNA methyltransferase expression was confirmed in these cases. The loss Of O-6-methylguanine-DNA methyltransferase expression was signifcantly associated with pTNM stage (P=0.037), tumour invasion (P-0.02), microsatellite instability (P=0.041) and overall survival (P=0.01). Among 11 gastric cancer cell lines, SNU-620 showed the loss of O-6-methylguanine-DNA methyltransferase expression as well as promoter methylation. After treatment with 5-aza-2-deoxycytidine, a demethylating agent, SNU-620 re-expressed O-6-methylguanine-DNA methyltransferase mRNA. In summary, we suggest that during gastric carcinogenesis, the loss of O-6-methylguanine-DNA methyltransferase expression frequently occurs via the hypermethylation of the CpG islands of the promoter region, and that this is significantly associated with the clinicopathological characteristics. (C) 2002 Cancer Research UK.