Cytoplasmic and nuclear accumulation of beta-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 activ ating T-cell factor (Tcf)/lymphoid enhancer factor (Lef)-regulated gene tra nscription. The level of beta -catenin is regulated through GSK-3 beta phos phorylation of specific serine and threonine residues, all of which are enc oded for in exon 3 of the beta -catenin gene (CTNNBI), Mutations altering t he GSK-3 beta phosphorylation sites lead to cellular accumulation of beta - catenin and constitutive transcription of Tcf/Lef target genes. Such mutati ons have previously been found in melanoma cell lines. In our study, primar y melanomas and their corresponding metastases were screened for CTNNBI exo n 3 mutations using single-strand conformation polymorphism and nucleotide sequence analysis. One of 31 primary tumors and 1 of 37 metastases, both or iginating from the same patient, had a TCT to TTT mutation at codon 45, cha nging serine to phenylalanine. Immunohistochemical analysis revealed membra nous localization of beta -catenin in a majority of the samples, The mutate d primary tumor and metastasis, however, displayed widespread cytoplasmic a nd nuclear expression of beta -catenin, An additional 30% of the primary tu mors showed focal cytoplasmic and nuclear staining. Thus, beta -catenin exo n 3 mutations are rare in primary as well as metastatic melanomas and do no t explain the abnormal cytoplasmic and nuclear localization of beta -cateni n round in a relatively large fraction of primary melanomas, (C) 2001 Wiley -Liss. Inc.