Expression of Fhit, Mlh1, p16INK4A and E-cadherin in early gastric neoplasia: Correlation with histological grade and gastric phenotype.
An increasing number of tumor suppressor genes (TSGs) that are inactivated by hypermethylation of CpG islands in the promoter have been reported in gastric carcinomas. The aim of this study is to evaluate the clinical significance of TSG protein expression, which correlates with the promoter status, methylated or not, during the early stages of gastric carcinogenesis and to examine its relationship with mucin phenotype. The protein expression of 4 TSGs including Fhit, Mlh1, p16INK4A and E-cadherin was examined using immunohistochemical methods in 103 early gastric neoplasias, comprising 41 adenomas and 62 intramucosal carcinomas, obtained by endoscopic mucosal resection. In addition, phenotypic expression patterns (gastric-, intestinal- and mixed-phenotypes) were also examined. The expression of Fhit, Mlh1, p16 and E-cadherin was lost or reduced in 7.3, 12.2, 12.2 and 9.8% of the adenomas and in 35.5, 29.0, 29.0 and 32.3% of the intramucosal carcinomas, respectively. The absent expression of p16 was significantly associated with the degree of dysplasia in the adenomas (p=0.038). The average number of proteins among the 4 TSGs, whose expression was lost or reduced per sample, was significantly higher in the intramucosal carcinomas (1.35) than in the adenomas (0.41) (p=0.00013). Similarly, the average number was significantly higher in the gastric-type tumors (2.05) than in the intestinal-type tumors (0.49) (p=0.0000019). We demonstrated an increase in the number of TSG proteins whose expression is reduced or lost in the early stages of gastric tumorigenesis, and that this increase is associated with histological grade and gastric phenotype.
Hara
Akihito
A
Division of Medicine and Clinical Science, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan.
Yashima
Kazuo
K
Yasugi
Akiko
A
Koda
Masaharu
M
Kawaguchi
Koichiro
K
Harada
Kenichi
K
Andachi
Hironobu
H
Shiota
Goshi
G
Ito
Hisao
H
Murawaki
Yoshikazu
Y
D017766:Acid Anhydride Hydrolases / Q000235:genetics*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000236:Adenoma / Q000235:genetics / Q000473:pathology; D000368:Aged; D015820:Cadherins / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000473:pathology; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D013274:Stomach Neoplasms / Q000235:genetics*; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000099170:Bis(5'-adenosyl)triphosphatase; C501486:MLH1 protein, human