Mutations and nuclear accumulation of β‐catenin correlate with intestinal phenotypic expression in human gastric cancer

Abstract

Aims: Abnormal localization of β‐catenin is frequently observed in human gastric cancers. The aim of the present study was to evaluate relationships among gastrointestinal differentiation phenotypes, β‐catenin localization and mutations of Wnt signalling genes. Methods and results: Seventy‐seven regions in 39 gastric adenocarcinomas were classified according to β‐catenin localization and gastric and intestinal phenotypes. Cases with membranous β‐catenin localization showed a gradual decrease from gastric (G) (55% = 6/11) and gastric‐and‐intestinal‐mixed (GI) (17% = 5/29) to intestinal (I) (0% = 0/21) phenotypes, while those with nuclear localization showed a concomitant increase: 18% (2/11), 41% (12/29), 95% (20/21) and 63% (10/16) for G, GI, I and null type (N), respectively (P < 0.001, membranous versus nuclear localization in G, GI through I). Mutations in exon 3 of the β‐catenin gene were found in G (50% = 1/2), GI (67% = 8/12), I (45% = 9/20) and N (0% = 0/10) regions with nuclear β‐catenin localization (GI versus N, P < 0.01; I versus N, P < 0.05). Adenomatous polyposis coli (APC) gene mutations were demonstrated only in GI, I and N types, irrespective of β‐catenin localization. Molecular analysis of these genes revealed 10 tumours to be heterogeneous out of 16 informative cases (62.5%). Conclusion: Intestinal phenotypic expression is accompanied by a shift from membranous to cytoplasmic/nuclear accumulation of β‐catenin. In contrast, N‐type regions may progress along a different pathway.