The molecular basis of EPCAM expression loss in Lynch syndrome-associated tumors
The molecular basis of EPCAM expression loss in Lynch syndrome-associated tumors
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DOI：
10.1038/modpathol.2012.30
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发表时间：
2012-06-01
期刊：
影响因子：
7.5
通讯作者：
Blaker, Hendrik
中科院分区：
文献类型：
--
作者：
Huth, Cathrin;Kloor, Matthias;Blaker, Hendrik
影响上皮细胞粘附分子 (EPCAM) 基因的种系缺失会导致 MSH2 沉默并导致林奇综合征。我们最近报道，EPCAM 种系缺失的 Lynch 综合征患者的许多肿瘤（但并非所有肿瘤）都缺乏 EPCAM 表达。 EPCAM 表达的差异与 EPCAM 种系缺失的定位无关。因此，我们假设第二次体细胞攻击的类型（导致肿瘤发展过程中 MSH2 失活）决定了肿瘤细胞中 EPCAM 的表达。为了检验这一假设并评估林奇综合征相关腺瘤中是否已经检测到 EPCAM 表达缺乏，我们通过多重连接依赖性探针扩增分析了来自 EPCAM 种系缺失携带者的四种癌和两种腺瘤的 EPCAM 蛋白表达和 EPCAM 基因区域的等位基因缺失状态。在六分之四的肿瘤中，我们观察到缺乏 EPCAM 表达，并伴有影响 EPCAM 基因的双等位基因缺失。相反，在保留 EPCAM 蛋白表达的其余两个肿瘤中观察到 EPCAM 基因的单等位基因保留。这些结果表明，EPCAM 缺失携带者肿瘤中的 EPCAM 表达取决于使 MSH2 失活的第二个体细胞命中的定位。此外，我们报告结直肠腺瘤中缺乏 EPCAM 蛋白表达，这表明 EPCAM 免疫组织化学可以检测已经处于癌前阶段的 EPCAM 种系缺失。现代病理学(2012) 25, 911-916; doi:10.1038/modpathol.2012.30; 2012 年 3 月 2 日在线发布
Germline deletions affecting the Epithelial cell adhesion molecule (EPCAM) gene lead to silencing of MSH2 and cause Lynch syndrome. We have recently reported that lack of EPCAM expression occurs in many, but not all tumors from Lynch syndrome patients with EPCAM germline deletions. The differences in EPCAM expression were not related to the localization of EPCAM germline deletions. We therefore hypothesized that the type of the second somatic hit, which leads to MSH2 inactivation during tumor development, determines EPCAM expression in the tumor cells. To test this hypothesis and to evaluate whether lack of EPCAM expression can already be detected in Lynch syndrome-associated adenomas, we analyzed four carcinomas and two adenomas from EPCAM germline deletion carriers for EPCAM protein expression and allelic deletion status of the EPCAM gene region by multiplex ligation-dependent probe amplification. In four out of six tumors we observed lack of EPCAM expression accompanied by biallelic deletions affecting the EPCAM gene. In contrast, monoallelic retention of the EPCAM gene was observed in the remaining two tumors with retained EPCAM protein expression. These results demonstrate that EPCAM expression in tumors from EPCAM deletion carriers depends on the localization of the second somatic hit that inactivates MSH2. Moreover, we report lack of EPCAM protein expression in a colorectal adenoma, suggesting that EPCAM immunohistochemistry may detect EPCAM germline deletions already at a precancerous stage. Modern Pathology (2012) 25, 911-916; doi:10.1038/modpathol.2012.30; published online 2 March 2012