E-cadherin gene (CDH1) promoter methylation as the second hit in sporadic diffuse gastric carcinoma

In diffuse gastric carcinoma, despite common E-cadherin gene (CDH1) mutatio ns, tumors show absence of CDH1 loss of heterozigosity (LOH) in most cases. This observation challenges the classical two-hit model of tumor suppresse r gene inactivation. In order to investigate whether or not CDH1 promoter m ethylation may function as the second hit we analysed a series of 23 sporad ic gastric carcinomas for the presence of CDH1 mutations, CDH1 promoter met hylation, LOH and E-cadherin expression. CDH1 mutations were detected in ni ne of the 16 (56.3%) diffuse gastric carcinomas and in none of the seven in testinal gastric carcinomas. In diffuse gastric carcinomas harboring CDH1 m utations, LOH was observed in a single case. Loss of plasma membrane E-cadh erin expression was consistently found in all nine cases with CDH1 mutation , suggesting that tumors inactivated the remaining CDH1 allele via a differ ent mechanism. CDH1 promoter methylation was observed in nine of the 16 (56 .3%) diffuse-type gastric carcinoma cases, including six of the nine cases (66.7%) harboring CDH1 mutations. CDH1 promoter methylation was also seen i n two (28.6%) intestinal-type cases. Our results show that CDH1 promoter me thylation is the second hit in more than half of the sporadic diffuse gastr ic carcinoma cases harboring CDH1 mutations.