β-catenin mutation and expression analysis in ovarian cancer: Exon 3 mutations and nuclear translocation in 16% of endometrioid tumours

Abstract

The molecular mechanisms involved in the generation of epithelial ovarian cancers are poorly understood, but evidence suggests that the different histological subtypes may arise from independent tumorigenic events. β-Catenin is emerging as an important oncogene in the transformation of a number of epithelial cancers, and mutations have been reported in a small study of endometrioid ovarian adenocarcinomas. Mutations in the NH2-regulatory domain of β-catenin stabilise the cytoplasmic levels of this protein, which promotes up-regulation of the β-catenin-T-cell factor-lymphoid enhancer factor transcriptional complex. We report here β-catenin (CTNNBI) exon 3 mutation analysis in 149 epithelial ovarian carcinomas. This revealed 10/63 (16%) endometrioid ovarian tumours with activating mutations of the β-catenin gene. All mutations were missense changes within the GSK3β consensus site, affecting serine residues at codons 33 and 37 and glycine at codon 34. Immuno-histochemical analysis identified cytoplasmic stabilisation and nuclear translocation in those endometrioid tumours with mutations. This phenotypic change was also identified in 3 other endometrioid tumours that did not have somatic mutations within exon 3 of CTNNBI. Stabilisation of the free, monomeric pool of β-catenin and the probable resulting constitutive activation of its Tcf-associated transcriptional complex appears to be a specific oncogenic event in endometrioid ovarian adenocarci-noma. © 1999 Wiley-Liss, Inc.