Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
J Surg Oncol. 2012 Nov;106(6):777-82. doi: 10.1002/jso.23131. Epub 2012 Apr 18.
To explore the possible association between EBV, microsatellite instability (MSI), and alterations of hMLH1 protein, 282 tumors from 141 patients with multiple synchronous gastric carcinomas (MSGC) were studied.
In situ hybridization for EBV-encoded small RNA and hMLH1 immunohistochemistry were performed in tissue microarrays. In 19 MSGC cases with altered hMLH1 expression, methylation analyses by MethyLight and MSI tests were performed.
Loss of hMLH1 was found in 19 of 141 MSGC patients (13.5%) and 26 of 282 MSGC tumors (9.2%). hMLH1 loss was associated with differentiated histology (P = 0.03). Out of the 38 tumors from 19 hMLH1-negative MSGCs, 12 tumors from six cases (31.6%) showed concurrent methylation of hMLH1 and MSI-high in both multiple tumors. EBV was found in 31 of 141 MSGC patients (21.9%) and 49 of 282 MSGC tumors (17.4%) and was significantly associated with undifferentiated histology and a location within the upper third of the stomach (P < 0.002). EBV was not observed in any of the tumors that had a loss of hMLH1 expression.
Considering that EBV-associated GCs show global CpG island methylation, our findings suggest that EBV infection allows the gastric mucosa to escape from aberrant methylation of hMLH1 and induces a malignant pathway independent of MSI.
为了探索 EBV、微卫星不稳定性 (MSI) 和 hMLH1 蛋白改变之间可能存在的关联，对来自 141 例多发性胃同时性癌（MSGC）患者的 282 个肿瘤进行了研究。
在组织微阵列中进行 EBV 编码的小 RNA 的原位杂交和 hMLH1 免疫组织化学染色。在 19 例 hMLH1 表达改变的 MSGC 病例中，进行了 MethyLight 甲基化分析和 MSI 检测。
在 141 例 MSGC 患者中有 19 例（13.5%）和 282 例 MSGC 肿瘤中有 26 例（9.2%）存在 hMLH1 缺失。hMLH1 缺失与分化的组织学特征相关（P = 0.03）。在 19 例 hMLH1 阴性 MSGC 的 38 个肿瘤中，来自 6 例病例（31.6%）的 12 个肿瘤在多个肿瘤中均同时存在 hMLH1 甲基化和 MSI 高。在 141 例 MSGC 患者中有 31 例（21.9%）和 282 例 MSGC 肿瘤中有 49 例（17.4%）发现 EBV，与未分化的组织学特征和胃上部三分之一的位置显著相关（P < 0.002）。在任何 hMLH1 表达缺失的肿瘤中均未观察到 EBV。
考虑到 EBV 相关的 GC 表现为全基因组 CpG 岛甲基化，我们的研究结果表明 EBV 感染使胃黏膜逃脱 hMLH1 的异常甲基化，并诱导一条独立于 MSI 的恶性途径。
