Altered expression and mutation of beta-catenin gene in gastric carcinomasand cell lines

beta -Catenin serves not only as a structural component of the E-cadherin-m ediated cell-cell adhesion system, but also as a signaling molecule of the Wnt/wingless pathway. Deregulated expression of beta -catenin and mutations of the gene have been identified in a number of human malignancies, To det ermine the role of beta -catenin defects in stomach cancer, we investigated beta -catenin exon 3 mutations and altered protein expression in 77 primar y gastric carcinomas and 11 cell lines. In addition, the immunohistochemica l expression pattern of beta -catenin in 303 consecutive gastric cancers wa s determined and their relationships with clinicopathologic features and pa tient outcome were investigated, This study revealed 5% (4 of 77) tumors an d 27% (3 of 11) cell lines with beta -catenin gene alteration, 6 missense m utations, and 1 interstitial deletion. These genetic changes were shown to correlate closely with nuclear localization of the protein (p = 0.001). In an immunohistochemical analysis, abnormal expressions of beta -catenin, suc h as nuclear accumulation and loss of membranous distribution, were detecte d in 27% (81 of 303) of tumors overall. These altered beta -catenin express ions were more commonly observed in 37% (58 of 158) diffuse type gastric ca rcinomas (p < 0.001). Loss of membranous <beta>-catenin staining was associ ated with poor survival (p = 0.045), In conclusion, our results demonstrate that beta -catenin mutations are common in gastric cancer cell lines but o ccur infrequently in gastric carcinoma tissues, These mutations are one of the causes of the nuclear accumulation of beta -catenin, Frequent abnormali ties of beta -catenin expression in gastric carcinoma support the idea that both structural and signaling functions of the protein play a critical rol e in gastric carcinogenesis. (C) 2001 Wiley-Liss, Inc.