Corso G, Roviello F, Paredes J, Pedrazzani C, Novais M, Correia J, Marrelli D, Cirnes L, Seruca R, Oliveira C, Suriano G
Department of Human Pathology and Oncology, Division of Surgical Oncology, University of Siena, Siena, Italy.
Eur J Surg Oncol. 2007 Nov;33(9):1061-7. doi: 10.1016/j.ejso.2007.03.001. Epub 2007 Apr 16.
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.
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.
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.
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.
遗传性弥漫性胃癌（HDGC）是一种由E-钙黏蛋白种系突变引起的癌症易感性综合征。这些突变中有三分之一是错义类型，给遗传咨询带来了负担。最近在一个意大利HDGC家族中发现了一种新的种系错义突变（P373L）。本研究旨在确定P373L突变体的致病性质。
基于细胞聚集和侵袭试验评估P373L突变的影响。在E-钙黏蛋白基因座进行杂合性缺失（LOH）分析，寻找体细胞E-钙黏蛋白突变和启动子高甲基化，以确定肿瘤中E-钙黏蛋白野生型等位基因失活的机制。
在体外，P373L种系突变损害了E-钙黏蛋白的功能。在P373L突变携带者的肿瘤中观察到E-钙黏蛋白启动子高甲基化。
我们得出结论，临床、体外和分子遗传学数据的结合有助于对HDGC相关的CDH1种系错义突变进行准确分析，进而有助于对无症状突变携带者进行适当的临床管理。
