Bae S I, Lee H S, Kim S H, Kim W H
Department of Pathology, Seoul National University College of Medicine, 28 Yongon-dong, Seoul 110-799, Korea.
Br J Cancer. 2002 Jun 17;86(12):1888-92. doi: 10.1038/sj.bjc.6600372.
Promoter hypermethylation of CpG islands in tumour suppressor genes can lead to transcriptional inactivation. To investigate the association between methylation and expression at O6-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 O6-methylguanine-DNA methyltransferase expression and the clinical data, we investigated O6-methylguanine-DNA methyltransferase expression in 315 consecutive gastric carcinomas. A similar frequency of loss of O6-methylguanine-DNA methyltransferase expression was confirmed in these cases. The loss of O6-methylguanine-DNA methyltransferase expression was significantly 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 O6-methylguanine-DNA methyltransferase expression as well as promoter methylation. After treatment with 5-aza-2-deoxycytidine, a demethylating agent, SNU-620 re-expressed O6-methylguanine-DNA methyltransferase mRNA. In summary, we suggest that during gastric carcinogenesis, the loss of O6-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.
肿瘤抑制基因中CpG岛的启动子高甲基化可导致转录失活。为了研究O6-甲基鸟嘌呤-DNA甲基转移酶甲基化与表达之间的关联，我们对149例胃癌进行了甲基化特异性PCR和免疫组织化学检测。在14.1%的肿瘤中发现启动子甲基化，在11.4%的肿瘤中检测到表达缺失。为了研究O6-甲基鸟嘌呤-DNA甲基转移酶表达与临床数据之间的相关性，我们对315例连续的胃癌进行了O6-甲基鸟嘌呤-DNA甲基转移酶表达研究。在这些病例中证实了O6-甲基鸟嘌呤-DNA甲基转移酶表达缺失的频率相似。O6-甲基鸟嘌呤-DNA甲基转移酶表达缺失与pTNM分期（P = 0.037）、肿瘤浸润（P = 0.02）、微卫星不稳定性（P = 0.041）和总生存期（P = 0.01）显著相关。在11种胃癌细胞系中，SNU-620显示出O6-甲基鸟嘌呤-DNA甲基转移酶表达缺失以及启动子甲基化。用去甲基化剂5-氮杂-2'-脱氧胞苷处理后，SNU-620重新表达O6-甲基鸟嘌呤-DNA甲基转移酶mRNA。总之，我们认为在胃癌发生过程中，O6-甲基鸟嘌呤-DNA甲基转移酶表达缺失经常通过启动子区域CpG岛的高甲基化发生，并且这与临床病理特征显著相关。
