Aberrant DNA methylation precedes loss of heterozygosity on chromosome 16 in chronic hepatitis and liver cirrhosis
Aberrant DNA methylation precedes loss of heterozygosity on chromosome 16 in chronic hepatitis and liver cirrhosis
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DOI：
10.1016/s0304-3835(99)00316-x
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发表时间：
2000-01-01
期刊：
影响因子：
9.7
通讯作者：
Hirohashi, S
中科院分区：
文献类型：
--
作者：
Kanai, Y;Ushijima, S;Hirohashi, S
本研究的目的是探讨异常DNA甲基化在肝癌发生中的意义，其在遗传不稳定性中的参与是有争议的。采用38例肝细胞癌（HCC）患者的显微解剖肝标本，检测了位于16q22.1上的E-钙粘蛋白肿瘤抑制基因启动子周围区域的DNA甲基化状态，以及与E-钙粘蛋白基因座相邻的D16S421基因座的等位基因状态。几乎所有的非癌性肝组织都显示出与慢性肝炎和肝硬化相一致的组织学结果，这被认为是癌前状态。在61%的非癌肝组织中检测到DNA超甲基化。同时存在DNA高甲基化的HCC患者的非癌肝组织中DNA高甲基化的发生率（72%）显著高于无DNA高甲基化的HCC患者的非癌肝组织中DNA高甲基化的发生率（53%，P <0.05）。在35%的非癌肝组织中检测到D16 S421位点的杂合性丢失（洛）。肝癌患者的非癌肝组织中LOH的发生率为78%，而肝癌患者的非癌肝组织中未检测到LOH。52%的非癌肝组织同时存在或不存在DNA高甲基化和洛缺失，仅DNA高甲基化的发生率为41%。非癌肝组织中单纯洛缺失的发生率（7%）明显低于前两组（P <0.0001）。这些数据表明，异常的DNA甲基化参与了肝癌发生的癌前阶段，通过之前，或导致，洛缺失。(C)2000爱思唯尔科学爱尔兰有限公司保留所有权利。
The aim of this study was to examine the significance of aberrant DNA methylation, the participation of which in genetic instability is controversial, in hepatocarcinogenesis. The DNA methylation status of the region around the promoter of the E- cadherin tumor suppresser gene, which is located on 16q22.1, and the allelic status at the D16S421 locus, which is adjacent to the E-cadherin locus, were examined using microdissected liver specimens from 38 hepatocellular carcinoma (HCC) patients. Almost all of the non-cancerous liver tissues showed histological findings compatible with chronic hepatitis and cirrhosis, which are considered to be precancerous conditions. DNA hypermethylation was detected in 61% of the non-cancerous liver tissues. The incidence of DNA hypermethylation in the non-cancerous liver tissues of patients with HCCs also showing DNA hypermethylation (72%) was significantly higher than that of patients without DNA hypermethylation in their HCCs (53%, P < 0.05). Loss of heterozygosity (LOH) at the D16S421 locus was detected in 35% of the non-cancerous liver tissues. The incidence of LOH in the non-cancerous liver tissues of patients with HCCs also showing LOH was 78%, whereas LOH was not detected in non-cancerous liver tissues of patients without LOH in their HCCs. Fifty-two percent of the non-cancerous liver tissues showed both or neither of DNA hypermethylation and LOH; the incidence of DNA hypermethylation alone in noncancerous Liver tissue was 41%. The incidence of LOH alone in non-cancerous liver tissue (7%) was significantly lower compared to those of the former two cases (P < 0.0001). These data suggest that aberrant DNA methylation participates in the precancerous stage of hepatocarcinogenesis by preceding, or causing, LOH. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.