Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma
Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma
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DOI：
10.1073/pnas.95.12.6870
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发表时间：
1998-06-09
影响因子：
11.1
通讯作者：
Baylin, SB
中科院分区：
文献类型：
--
作者：
Herman, JG;Umar, A;Baylin, SB
参与 DNA 错配修复的基因失活与结直肠癌中的微卫星不稳定性 (MSI) 有关。我们报告说，在大多数伴有 MSI 的散发性原发性结直肠癌中发现了 hMLH1 5' CpG 岛的高甲基化，并且这种甲基化经常但并非总是与 hMLH1 蛋白表达缺失相关。这种甲基化也发生在 MSI- 肿瘤以及具有已知错配修复基因 (MMR) 突变的 MSI+ 肿瘤中，但不太常见。未发现 hMSH2 过度甲基化。伴有 MSI 的结直肠癌细胞系的高甲基化也经常被观察到，在这种情况下，用 5-aza-2'-deoxycytidine 逆转甲基化不仅会导致 hMLH1 蛋白的重新表达，而且还会恢复 MMR 缺陷细胞系的 MMR 能力。我们的结果表明，散发性结直肠癌中的微卫星不稳定性通常是由于与 DNA 甲基化相关的 hMLH1 表观遗传失活所致。
Inactivation of the genes involved in DNA mismatch repair is associated with microsatellite instability (MSI) in colorectal cancer. We report that hypermethylation of the 5' CpG island of hMLH1 is found in the majority of sporadic primary colorectal cancers with MSI, and that this methylation was often;but not invariably, associated with loss of hMLH1 protein expression. Such methylation also occurred, but was less common, in MSI- tumors, as well as in MSI+ tumors with known mutations of a mismatch repair gene (MMR). No hypermethylation of hMSH2 was found. Hypermethylation of colorectal cancer cell lines with MSI also was frequently observed, and in such cases, reversal of the methylation with 5-aza-2'-deoxycytidine not only resulted in reexpression of hMLH1 protein, but also in restoration of the MMR capacity in MMR-deficient cell lines. Our results suggest that microsatellite instability in sporadic colorectal cancer often results from epigenetic inactivation of hMLH1 in association with DNA methylation.