Loss of E-cadherin expression in gastric intestinal metaplasia and later stage p53 altered expression in gastric carcinogenesis.
Gastric cancers are commonly subdivided into intestinal and diffuse subtypes on a morphologic basis, supported by corollary evidence of differences at the pathogenetic and molecular levels. Chronic atrophic gastritis with intestinal metaplasia is a common precursor lesion for the intestinal type of carcinoma. To identify early molecular changes, in this study we have examined 13 surgical specimens both for the expression of E-cadherin, p53 and beta-catenin by immunohistochemistry and for methylation of the CDH1 promoter (E-cadherin) by bisulfite genomic sequencing of laser capture microdissected samples. Each specimen examined contained areas of normal (nonmetaplastic) gastric mucosa, as well as areas of intestinal metaplasia and/or carcinoma. Reduced or absent E-cadherin and partial to complete methylation of one to multiple CpG sites examined in the CDH1 promoter were observed in all of the metaplasia samples. Thus, the methylation status of the CDH1 promoter and expression of E-cadherin together provide strong evidence that loss of E-cadherin is an early event in intestinal type gastric carcinogenesis. In contrast, expression of p53, assumed to be mutant p53, was generally not detected (except for isolated cells) until the carcinoma stage in tissues from these patients. These results suggest that mutation of p53 is a late event in intestinal type gastric cancer. The level of beta-catenin expression did not appear to change between normal, metaplastic and carcinoma cells of intestinal type, and no nuclear staining was visible in any of the tissues. These results suggest that the Wnt signaling pathway is not upregulated in this type of cancer.
Ma
M
M
Laboratory of Experimental Pathology and NIEHS, NIH, Research Triangle Park, NC 27709, USA.
Devereux
T R
TR
Stockton
P
P
Sun
K
K
Sills
R C
RC
Clayton
N
N
Portier
M
M
Flake
G
G
D000230:Adenocarcinoma / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D015820:Cadherins / Q000032:analysis / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000032:analysis / Q000378:metabolism; D017931:DNA Primers / Q000032:analysis; D004273:DNA, Neoplasm / Q000032:analysis; D004210:Dissection / Q000379:methods; D005753:Gastric Mucosa / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D016480:Helicobacter pylori / Q000302:isolation & purification / Q000472:pathogenicity; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008679:Metaplasia / Q000378:metabolism / Q000473:pathology; D008745:Methylation; D008846:Micromanipulation; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions; D013274:Stomach Neoplasms / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000378:metabolism*; D051176:beta Catenin
C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D017931:DNA Primers; D004273:DNA, Neoplasm; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin