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

The molecular mechanisms involved in the generation of epithelial ovarian c ancers are poorly understood, but evidence suggests that the different hist ological subtypes may arise from independent tumorigenic events, beta-caten in is emerging as an important oncogene in the transformation of a number o f epithelial cancers, and mutations have been reported in a small study of endometrioid ovarian adenocarcinomas. Mutations in the NH2-regulatory domai n of beta-catenin stabilise the cytoplasmic levels of this protein, which p romotes up-regulation of the beta-catenin-T-cell factor-lymphoid enhancer f actor transcriptional complex. We report here beta-catenin (CTNNBI) exon 3 mutation analysis in 149 epithelial ovarian carcinomas. This revealed 10/63 (16%) endometrioid ovarian tumours with activating mutations of the beta-c atenin gene. All mutations were missense changes within the GSK3 beta conse nsus site, affecting serine residues at codons 33 and 37 and glycine at cod on 34. Immuno-histochemical analysis identified cytoplasmic stabilisation a nd 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 t he free, monomeric pool of beta-catenin and the probable resulting constitu tive activation of its Tcf-associated transcriptional complex appears to be a specific oncogenic event in endometrioid ovarian adenocarcinoma. Int. J. Cancer 82:625-629, 1999. (C) 1999 Wiley-Liss, Inc.