Methylation of hMLH1 promoter correlates with the gene silencing with a region-specific manner in colorectal cancer.
Methylation of hMLH1 promoter correlates with the gene silencing with a region-specific manner in colorectal cancer.
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DOI：
10.1038/sj.bjc.6600148
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发表时间：
2002-02-12
影响因子：
8.8
通讯作者：
Kim, Y S
中科院分区：
文献类型：
--
作者：
Deng, G;Peng, E;Gum, J;Terdiman, J;Sleisenger, M;Kim, Y S
80%以上的遗传性非息肉病性结直肠癌和15-20%的散发性结直肠癌存在微卫星不稳定性。微卫星不稳定性是由错配修复基因失活引起的，如主要是hMLH 1，hMSH 2。为探讨错配修复基因在结直肠癌中失活的机制，特别是hMLH 1基因启动子区域特异性甲基化及其与基因表达的相关性，我们分析了结直肠癌组织中hMLH 1基因的微卫星不稳定性、hMLH 1基因的表达、甲基化和杂合性缺失。71例原发性结直肠癌中有17例存在微卫星不稳定性，包括39例粘液癌中的14例（36%）和32例非粘液癌中的3例（9%）。16例微卫星不稳定性肿瘤中分别有9例和3例hMLH 1和hMSH 2表达缺失。在hMLH 1启动子近端区域的CpG位点的甲基化检测在9个肿瘤中的7个没有表现出hMLH 1的表达，而没有甲基化存在于正常粘膜和肿瘤表达hMLH 1。然而，在包括正常粘膜和hMLH 1表达肿瘤的所有组织中观察到远端区域的甲基化。这一观察结果表明，hMLH 1启动子甲基化在微卫星不稳定性中起重要作用，并具有区域特异性。hMLH 1基因杂合性缺失存在于17个细胞系中的4个和54个hMLH 1状态正常的肿瘤中的16个中，而杂合性缺失在所有9个细胞系和9个hMLH 1状态异常的肿瘤（突变或表达缺失）中不存在，表明杂合性缺失不常参与散发性结直肠癌中hMLH 1基因的失活。英国癌症杂志（2002）86，574-579。DOI：10.1038/sj/bjc/6600148 www.bjcancer.com © 2002英国癌症研究中心
Microsatellite instability is present in over 80% of the hereditary non-polyposis colorectal carcinoma and about 15–20% of the sporadic cancer. Microsatellite instability is caused by the inactivation of the mismatch repair genes, such as primarily hMLH1, hMSH2. To study the mechanisms of the inactivation of mismatch repair genes in colorectal cancers, especially the region-specific methylation of hMLH1 promoter and its correlation with gene expression, we analysed microsatellite instability, expression and methylation of hMLH1 and loss of heterozygosity at hMLH1 locus in these samples. Microsatellite instability was present in 17 of 71 primary tumours of colorectal cancer, including 14 of 39 (36%) mucinous cancer and three of 32 (9%) non-mucinous cancer. Loss of hMLH1 and hMSH2 expression was detected in nine and three of 16 microsatellite instability tumours respectively. Methylation at CpG sites in a proximal region of hMLH1 promoter was detected in seven of nine tumours that showed no hMLH1 expression, while no methylation was present in normal mucosa and tumours which express hMLH1. However, methylation in the distal region was observed in all tissues including normal mucosa and hMLH1 expressing tumours. This observation indicates that methylation of hMLH1 promoter plays an important role in microsatellite instability with a region-specific manner in colorectal cancer. Loss of heterozygosity at hMLH1 locus was present in four of 17 cell lines and 16 of 54 tumours with normal hMLH1 status, while loss of heterozygosity was absent in all nine cell lines and nine tumours with abnormal hMLH1 status (mutation or loss of expression), showing loss of heterozygosity is not frequently involved in the inactivation of hMLH1 gene in sporadic colorectal cancer. British Journal of Cancer (2002) 86, 574–579. DOI: 10.1038/sj/bjc/6600148 www.bjcancer.com © 2002 Cancer Research UK