Characterization of the P373L E-cadherin germline missense mutation and implication for clinical management
Characterization of the P373L E-cadherin germline missense mutation and implication for clinical management
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DOI：
10.1016/j.ejso.2007.03.001
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发表时间：
2007-11-01
期刊：
影响因子：
3.8
通讯作者：
Suriano, G.
中科院分区：
文献类型：
--
作者：
Corso, G.;Roviello, F.;Suriano, G.
目的：遗传性弥漫性胃癌（HDGC）是一种由E-钙粘蛋白（E-cadherin）基因突变引起的肿瘤易感综合征。这些突变中有三分之一是错义突变，这是遗传咨询的负担。最近在一个HDGC意大利家系中发现了一个新的生殖系错义突变（P373 L）。目前的工作旨在解决P373 L突变体的致病性。方法：P373 L突变效应的评估是基于细胞聚集和侵袭试验。通过对E-cadherin基因座的洛缺失分析、体细胞E-cadherin突变和启动子甲基化研究，探讨E-cadherin野生型等位基因在肿瘤中失活的机制。E-cadherin启动子甲基化观察肿瘤的P373 L突变carrier.Conclusion：我们得出结论，临床，体外和分子遗传学数据的组合是有助于建立一个准确的分析HDGC相关的CDH 1种系错义突变，随后为适当的临床管理无症状突变载体。(c)2007爱思唯尔有限公司保留所有权利。
Aim: Hereditary diffuse gastric cancer (HDGC) is a cancer susceptibility syndrome caused by E-cadherin germline mutations. One-third of these mutations are of the missense type, representing a burden in genetic counselling. A new germline missense mutation (P373L) was recently identified in a HDGC Italian family. The present work aimed at addressing the disease-causative nature of the P373L mutant.Methods: Assessment of the P373L mutation effect was based on cell aggregation and invasion assays. LOH analysis at the E-cadherin locus, search for somatic E-cadherin mutations and for promoter hypermethylation were performed to identify the mechanism of inactivation of the E-cadherin wild-type allele in the tumour.Results: In vitro the P373L germline mutation impaired the E-cadherin functions. E-cadherin promoter hypermethylation was observed in the tumour of the P373L mutation carrier.Conclusion: We conclude that the combination of clinical, in vitro and molecular genetic data is helpful for establishing an accurate analysis of HDGC-associated CDH1 germline missense mutations and subsequently for appropriate clinical management of asymptomatic mutation carriers. (c) 2007 Elsevier Ltd. All rights reserved.