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) mutations, tumors show absence of CDH1 loss of heterozigosity (LOH) in most cases. This observation challenges the classical two-hit model of tumor suppressor gene inactivation. In order to investigate whether or not CDH1 promoter methylation may function as the second hit we analysed a series of 23 sporadic gastric carcinomas for the presence of CDH1 mutations, CDH1 promoter methylation, LOH and E-cadherin expression. CDH1 mutations were detected in nine of the 16 (56.3%) diffuse gastric carcinomas and in none of the seven intestinal gastric carcinomas. In diffuse gastric carcinomas harboring CDH1 mutations, LOH was observed in a single case. Loss of plasma membrane E-cadherin expression was consistently found in all nine cases with CDH1 mutation, suggesting that tumors inactivated the remaining CDH1 allele via a different 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 in two (28.6%) intestinal-type cases. Our results show that CDH1 promoter methylation is the second hit in more than half of the sporadic diffuse gastric carcinoma cases harboring CDH1 mutations.
Machado
J C
JC
IPATIMUP, 4200 Porto, Portugal.
Oliveira
C
C
Carvalho
R
R
Soares
P
P
Berx
G
G
Caldas
C
C
Seruca
R
R
Carneiro
F
F
Sobrinho-Simöes
M
M
D000230:Adenocarcinoma / Q000209:etiology / Q000235:genetics*; D015820:Cadherins / Q000235:genetics*; D019175:DNA Methylation; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000209:etiology / Q000235:genetics*
D015820:Cadherins