Identification of CDH1 germline missense mutations associated with functional inactivation of the E-cadherin protein in young gastric cancer probands
Identification of CDH1 germline missense mutations associated with functional inactivation of the E-cadherin protein in young gastric cancer probands
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DOI：
10.1093/hmg/ddg048
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发表时间：
2003-03-01
影响因子：
3.5
通讯作者：
Seruca, R
中科院分区：
文献类型：
--
作者：
Suriano, G;Oliveira, C;Seruca, R
E-钙粘附素参与细胞连接的形成和上皮完整性的维持。遗传性弥漫性胃癌(HDGC)中发现了E-钙粘素基因(CDH1)的种系突变失活，这直接证明了E-钙粘素基因突变触发了肿瘤的发生。我们筛选了一系列66名年轻的胃癌先证者的种系CDH1突变，发现了两个新的错义改变和一个内含子变异。然后，我们分析了这里发现的两个外显子错义变体以及我们之前在HGDC家族中发现的第三个生殖系错义变体的功能意义。将编码野生型和突变型E-钙粘蛋白的cDNA稳定地导入中国仓鼠卵巢E-钙粘素阴性细胞。对转染的细胞株进行了聚集、运动和侵袭能力的检测。我们的研究表明，部分明显的散发性早发性弥漫性胃癌与E-钙粘蛋白基因的胚系改变有关。我们还证明了一定比例的错义变异与显著的功能后果有关，这表明我们的细胞模型可以作为辅助工具来确定已识别的E-钙粘蛋白胚系改变的潜在致病作用。
E-cadherin is involved in the formation of cell-junctions and the maintenance of epithelial integrity. Direct evidence of E-cadherin mutations triggering tumorigenesis has come from the finding of inactivating germline mutations of the gene (CDH1) in hereditary diffuse gastric cancer (HDGC). We screened a series of 66 young gastric cancer probands for germline CDH1 mutations, and two novel missense alterations together with an intronic variant were identified. We then analysed the functional significance of the two exonic missense variants found here as well as a third germline missense variant that we previously identified in a HGDC family. cDNAs encoding either the wild-type protein or mutant forms of E-cadherin were stably transfected into CHO (Chinese hamster ovary) E-cadherin-negative cells. Transfected cell-lines were characterized in terms of aggregation, motility and invasion. We show that a proportion of apparently sporadic early-onset diffuse gastric carcinomas are associated with germline alterations of the E-cadherin gene. We also demonstrate that a proportion of missense variants are associated with significant functional consequences, suggesting that our cell model can be used as an adjunct in deciding on the potential pathogenic role of identified E-cadherin germline alterations.