Hypermethylation of the hMLH1 gene promoter in human gastric cancers with microsatellite instability.
Hypermethylation of the hMLH1 gene promoter in human gastric cancers with microsatellite instability.
复制标题
DOI：
--
复制
发表时间：
1999-03
期刊：
影响因子：
11.2
通讯作者：
A. Fleisher;M. Esteller;Suna Wang;G. Tamura;Hiroyuki Suzuki;Jing Yin;T. Zou;J. Abraham;D. Kong
中科院分区：
文献类型：
--
作者：
A. Fleisher;M. Esteller;Suna Wang;G. Tamura;Hiroyuki Suzuki;Jing Yin;T. Zou;J. Abraham;D. Kong
与任何其他类型的散发性人类癌症相比，人类胃癌显示出更高的微卫星不稳定性（MSI）患病率。 MSI 如此高频率的原因尚不清楚。与子宫内膜癌和结直肠癌相反，DNA错配修复（MMR）基因hMLH1或hMSH2的突变在胃癌中尚未被描述。然而，hMLH1 MMR 基因启动子的高甲基化在 MSI 阳性子宫内膜癌和结直肠癌中相当常见。这种高甲基化与 hMLH1 转录阻断有关，而 hMLH1 转录阻断可通过去甲基化而逆转，表明表观遗传机制是 hMLH1 基因失活和 MMR 缺陷的基础。因此，我们研究了总共 65 个胃肿瘤中 hMLH1 启动子高甲基化的患病率：18 个 MSI 频繁（MSI-H），8 个 MSI 不频繁（MSI-L），39 个 MSI 阴性。我们发现 hMLH1 启动子高甲基化与 MSI 之间存在显着关联；在 18 个 MSI-H 肿瘤中，14 个（77.8%）显示高甲基化，而 8 个 MSI-L 肿瘤中有 6 个（75%）在 hMLH1 处显示高甲基化。相比之下，39 个 MSI 阴性肿瘤中只有 1 个 (2.6%) 表现出 hMLH1 高甲基化（与 MSI 阴性相比，MSI-H 或 MSI-L 的 P<0.0001）。此外，通过免疫组织化学和蛋白质印迹法，高甲基化的癌症显示 hMLH1 蛋白的表达减少，而非高甲基化的肿瘤则表达丰富的 hMLH1 蛋白。这些数据表明 hMLH1 的高甲基化与胃癌中的 MSI 密切相关，并表明在这组癌症中发生 MMR 缺陷的表观遗传机制。
Human gastric carcinoma shows a higher prevalence of microsatellite instability (MSI) than does any other type of sporadic human cancer. The reasons for this high frequency of MSI are not yet known. In contrast to endometrial and colorectal carcinoma, mutations of the DNA mismatch repair (MMR) genes hMLH1 or hMSH2 have not been described in gastric carcinoma. However, hypermethylation of the hMLH1 MMR gene promoter is quite common in MSI-positive endometrial and colorectal cancers. This hypermethylation has been associated with hMLH1 transcriptional blockade, which is reversible with demethylation, suggesting that an epigenetic mechanism underlies hMLH1 gene inactivation and MMR deficiency. Therefore, we studied the prevalence of hMLH1 promoter hypermethylation in a total of 65 gastric tumors: 18 with frequent MSI (MSI-H), 8 with infrequent MSI (MSI-L), and 39 that were MSI negative. We found a striking association between hMLH1 promoter hypermethylation and MSI; of 18 MSI-H tumors, 14 (77.8%) showed hypermethylation, whereas 6 of 8 MSI-L tumors (75%) were hypermethylated at hMLH1. In contrast, only 1 of 39 (2.6%) MSI-negative tumors demonstrated hMLH1 hypermethylation (P<0.0001 for MSI-H or MSI-L versus MSI-negative). Moreover, hypermethylated cancers demonstrated diminished expression of hMLH1 protein by both immunohistochemistry and Western blotting, whereas nonhypermethylated tumors expressed abundant hMLH1 protein. These data indicate that hypermethylation of hMLH1 is strongly associated with MSI in gastric cancers and suggest an epigenetic mechanism by which defective MMR occurs in this group of cancers.