Combined analysis of E-cadherin gene (CDH1) promoter hypermethylation and E-cadherin protein expression in patients with gastric cancer: implications for treatment with demethylating drugs.
BACKGROUND
Hypermethylation is studied as a new, relevant mechanism for silencing tumor suppressor genes. It is a potentially reversible epigenetic change and it is the target of novel anticancer compounds with demethylating activity. In this perspective, we investigated E-cadherin gene (CDH1) promoter hypermethylation in gastric carcinomas and its correlation with E-cadherin protein expression.


METHODS
Consecutive cases of gastric carcinoma with assessable paraffin-embedded tumor blocks and paired normal mucosa were considered eligible for study entry. CDH1 promoter hypermethylation and E-cadherin protein expression were determined by methylation-specific polymerase chain reaction and immunohistochemistry, respectively.


RESULTS
CDH1 promoter hypermethylation was found in 20 out of 70 gastric carcinomas and the epigenetic change occurred in the early, as well as in the locally advanced disease. In five cases, hypermethylation was also detected in the normal mucosa. Eighteen out of 20 hypermethylated tumors were of the diffuse histotype (P=0.0001). Of 24 tumors with reduced or negative E-cadherin expression, 19 were hypermethylated and 5 were unmethylated (P=0.0001).


CONCLUSIONS
CDH1 promoter hypermethylation frequently occurs in gastric carcinomas of the diffuse histotype and it is significantly associated with downregulated E-cadherin expression. The knowledge on the hypermethylation status of tumor suppressor genes may be relevant to the development of demethylating drugs and novel chemopreventive strategies in solid tumors.
Graziano
F
F
Medical Oncology Unit, Hospital of Urbino, Italy. frada@tin.it
Arduini
F
F
Ruzzo
A
A
Mandolesi
A
A
Bearzi
I
I
Silva
R
R
Muretto
P
P
Testa
E
E
Mari
D
D
Magnani
M
M
Scartozzi
M
M
Cascinu
S
S
D000328:Adult; D000368:Aged; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D005753:Gastric Mucosa / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016612:Paraffin Embedding; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
D015820:Cadherins; D004247:DNA