Kanai Y, Ushijima S, Tsuda H, Sakamoto M, Sugimura T, Hirohashi S
Pathology Division, National Cancer Center Research Institute, Tsukiji, Tokyo.
Jpn J Cancer Res. 1996 Dec;87(12):1210-7. doi: 10.1111/j.1349-7006.1996.tb03135.x.
In order to clarify the significance of DNA methylation in both earlier and later stages of hepatocarcinogenesis, the DNA methylation state on chromosome 16, on which loss of heterozygosity (LOH) has frequently been detected in human hepatocellular carcinomas (HCCs), was examined. DNA from primary HCCs and tissues showing chronic hepatitis and liver cirrhosis, which are considered to be precancerous conditions, was analyzed by digestion with methylation-sensitive and non-sensitive restriction enzymes. DNA hypermethylation at the D16S32, tyrosine aminotransferase (TAT) and D16S7 loci and hypomethylation at the D16S4 locus were detected in 18%, 58%, 20% and 48% of examined HCCs, respectively. Aberrant DNA methylation occurred more frequently in advanced HCCs than in early HCCs. Moreover, DNA hypermethylation at the D16S32, TAT and D16S7 loci was frequently observed in chronic hepatitis and liver cirrhosis. The incidence of DNA hypermethylation was higher than that of LOH (42% at the TAT locus). These data suggest that DNA hypermethylation might predispose the locus to allelic loss. Aberrant DNA methylation is a significant change which may participate in the early developmental stages of HCCs.
为了阐明DNA甲基化在肝癌发生早期和晚期阶段的意义，对16号染色体上的DNA甲基化状态进行了检测，在人类肝细胞癌（HCC）中经常检测到该染色体上的杂合性缺失（LOH）。通过用甲基化敏感和不敏感的限制性内切酶消化，分析了原发性肝癌以及显示慢性肝炎和肝硬化的组织（这些被认为是癌前病变）的DNA。在所检测的肝癌中，分别有18%、58%、20%和48%检测到D16S32、酪氨酸转氨酶（TAT）和D16S7位点的DNA高甲基化以及D16S4位点的低甲基化。异常DNA甲基化在晚期肝癌中比在早期肝癌中更频繁地出现。此外，在慢性肝炎和肝硬化中经常观察到D16S32、TAT和D16S7位点的DNA高甲基化。DNA高甲基化的发生率高于LOH的发生率（TAT位点为42%）。这些数据表明，DNA高甲基化可能使该位点易发生等位基因缺失。异常DNA甲基化是一个可能参与肝癌早期发展阶段的重要变化。
