Cytoplasmic and nuclear accumulation of β-catenin is rarely caused by CTNNB1 exon 3 mutations in cutaneous malignant melanoma

beta -catenin plays an important role in the Wnt signaling pathway by activating T-cell factor (Tcf)/lymphoid enhancer factor (Lef)-regulated gene transcription. The level of beta -catenin is regulated through GSK-3 beta phosphorylation of specific serine and threonine residues, all of which are encoded for in exon 3 of the beta -catenin gene (CTNNBI), Mutations altering the GSK-3 beta phosphorylation sites lead to cellular accumulation of beta -catenin and constitutive transcription of Tcf/Lef target genes. Such mutations have previously been found in melanoma cell lines. In our study, primary melanomas and their corresponding metastases were screened for CTNNBI exon 3 mutations using single-strand conformation polymorphism and nucleotide sequence analysis. One of 31 primary tumors and 1 of 37 metastases, both originating from the same patient, had a TCT to TTT mutation at codon 45, changing serine to phenylalanine. Immunohistochemical analysis revealed membranous localization of beta -catenin in a majority of the samples, The mutated primary tumor and metastasis, however, displayed widespread cytoplasmic and nuclear expression of beta -catenin, An additional 30% of the primary tumors showed focal cytoplasmic and nuclear staining. Thus, beta -catenin exon 3 mutations are rare in primary as well as metastatic melanomas and do not explain the abnormal cytoplasmic and nuclear localization of beta -catenin round in a relatively large fraction of primary melanomas, (C) 2001 Wiley-Liss. Inc.