Microsatellite instability in thorotrast-induced human intrahepatic cholangiocarcinoma
Microsatellite instability in thorotrast-induced human intrahepatic cholangiocarcinoma
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DOI：
10.1002/ijc.10726
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发表时间：
2002-12-01
影响因子：
6.4
通讯作者：
Fukumoto, M
中科院分区：
文献类型：
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作者：
Liu, D;Momoi, H;Fukumoto, M
Thorotrast 是一种放射性 (ThO2)-Th-232 的胶体悬浮液，可发射颗粒，在第二次世界大战期间被用作射线照相造影剂。众所周知，注射后数十年会诱发肝癌，最常见的是 ICC。由于辐射会导致基因组不稳定，因此我们分析了 Thorotrast 诱导的 ICC 中的 MSI。 Thorotrast ICC 中 MSI+ 病例的频率为 623%，而非 Thorotrast ICC 中为 22.7%。然而，在 Thorotrast ICC 中没有观察到单核苷酸重复的移码突变。此外，MSI+表型与Thorotrast的沉积量或ICC诱导的潜伏期无关。与 Thorotrast ICC 中邻近的非肿瘤部分相比，hMLHI 和 hMSH2 MMR 基因的启动子区域在肿瘤部分往往高度甲基化。 hMLHI 启动子的甲基化与 Thorotrast ICC 中的 MSI+ 表型相关。相反，在非 Thorotrast ICC 病例中，这些启动子区域的甲基化状态与 MSI 无关。这些发现表明，暴露于 Thorotrast 引起的 MSI 主要反映了癌细胞的克隆扩张，部分原因是 hMLHI 因高甲基化而失活。 (C) 2002 Wiley-Liss, Inc.
Thorotrast, a colloidal suspension of radioactive (ThO2)-Th-232 that emits of particles, was used as a radiographic contrast during World War II. It is known to induce liver cancers, most frequently ICC, decades after injection. Since radiation induces genomic instability, we analyzed MSI in Thorotrast-induced ICC. The frequency of MSI+ cases was 623% in Thorotrast ICC, whereas it was 22.7% in non-Thorotrast ICC. However, frameshift mutations of mononucleotide repeats were not observed in Thorotrast ICC. In addition, the MSI+ phenotype was not associated with the quantity of Thorotrast deposited or the latency period of ICC induction. Promoter regions of both the hMLHI and the hMSH2 MMR genes tended to be hypermethylated in the tumor part compared to the adjacent nontumor part in Thorotrast ICC. Methylation of the hMLHI promoter was associated with the MSI+ phenotype in Thorotrast ICC. In contrast, methylation status of these promoter regions was not related to MSI in non-Thorotrast ICC cases. These findings suggest that MSI induced by exposure to Thorotrast mainly reflects clonal expansion of cancer cells and is partly due to inactivation of hMLHI by hypermethylation. (C) 2002 Wiley-Liss, Inc.