Concerted promoter hypermethylation of hMLH1, p16INK4A, and E-cadherin in gastric carcinomas with microsatellite instability
Concerted promoter hypermethylation of hMLH1, p16INK4A, and E-cadherin in gastric carcinomas with microsatellite instability
复制标题
DOI：
10.1002/path.1325
复制
发表时间：
2003-05-01
影响因子：
7.3
通讯作者：
Kim, H
中科院分区：
文献类型：
--
作者：
Kim, H;Kim, YH;Kim, H
在大多数散发性胃癌中，微卫星不稳定性（MSI）起源于hMLH 1基因启动子超甲基化导致的失活。然而，其他基因的甲基化模式及其在高NISI（NISI-H）胃癌的后果还没有得到很好的表征。为探讨MSI-H胃癌启动子甲基化的异常，检测了36例NISI-H胃癌中6个基因（hMLH 1、p16（INK 4A）、E-cadherin、Rb、RASSF 1A和VHL）启动子甲基化和CpG岛甲基化表型（CIMP），并与43例微卫星稳定（MSS）胃癌进行比较。在hMLH 1、p16（INK 4A）和E-cadherin中发现频繁的启动子高甲基化，并且在MSI-H胃癌中的频率显著更高。hMLH 1、E-cadherin和p16（INK 4A）的启动子高甲基化分别见于89%、78%和33%的NISI-H胃癌和16%、32%和11%的MSS癌（p = 0.01）。在MSI-H癌中发现hNILH 1和p16（INK 4A）与高甲基化启动子相关的基因产物的选择性缺失或表达降低，而在MSI-H和MSS癌中E-钙粘蛋白的表达普遍降低。MSI-H胃癌也与高CIMP（CIMP-H，检查的5个位点中有3个或3个以上显示甲基化）相关。22例（61%）MSI-H胃癌为CIMP-H，而只有7例（16%）MSS癌（p = 0.001）。这些发现表明hMLH 1是CIMP-H胃癌中常见的甲基化靶点之一，并且通过启动子超甲基化使hMLH 1失活会导致肿瘤遵循MSI途径。版权所有（C）2003约翰威利父子有限公司。
In most sporadic gastric carcinomas, microsatellite instability (MSI) originates from inactivation of the hMLH1 gene by promoter hypermethylation. However, the methylation patterns of other genes and their consequences in high NISI (NISI-H) gastric carcinomas are not well characterized. To address the aberrant promoter methylation profiles of MSI-H gastric carcinomas, promoter methylation of six genes (hMLH1, p16(INK4A), E-cadherin, Rb, RASSF1A, and VHL) and CpG island methylator phenotype (CIMP) were explored in 36 NISI-H gastric carcinomas and the results were compared with those of 43 microsatellite-stable (MSS) gastric carcinomas. Frequent promoter hypermethylation was found in hMLH1, p16(INK4A), and E-cadherin and the frequency was significantly higher in MSI-H gastric carcinomas. Promoter hypermethylation of hMLH1, E-cadherin, and p16(INK4A) was found in 89%, 78%, and 33% of NISI-H gastric carcinomas and in 16%, 32%, and 11% of MSS carcinomas, respectively (p = 0.01). Selective absent or decreased expression of the gene product related to the hypermethylated promoter was found for hNILH1 and p16(INK4A) in MSI-H carcinoma, whereas the expression of E-cadherin was generally decreased both in the MSI-H and in the MSS carcinomas. MSI-H gastric carcinomas were also related to the high CIMP (CIMP-H, three or more of the five loci examined showing methylation). Twenty-two (61%) MSI-H gastric carcinomas were CIMP-H, compared with only seven (16%) MSS carcinomas (p = 0.001). These findings indicate that hMLH1 is one of the frequent methylation targets in CIMP-H gastric carcinomas and that inactivation of hMLH1 through promoter hypermethylation results in tumours following the MSI pathway. Copyright (C) 2003 John Wiley Sons, Ltd.