title: Concomitant activation of Wnt pathway and loss of mismatch repair function in human melanoma.
abstract: Constitutive activation of the Wnt pathway plays a key role in the development of colorectal cancer and has also been implicated in the pathogenesis of other malignancies. Deregulation of Wnt signaling mainly occurs through genetic alterations of APC, the beta-catenin gene (CTNNB1), AXIN1 and AXIN2, leading to stabilization of beta-catenin. Physiologically, AXIN2 is transcriptionally induced on Wnt signaling activation and acts as a negative feedback regulator of the pathway. In colorectal cancer, mutations in CTNNB1 and AXIN2 occur preferentially in tumors with inactivation of the mismatch repair (MMR) genes MSH2, MLH1, or PMS2. In this study, the expression of beta-catenin and AXIN2, and the mutational status of CTNNB1, APC, and AXIN2 were evaluated in two MMR-deficient (PR-Mel and MR-Mel) and seven MMR-proficient human melanoma cell lines. Only PR-Mel and MR-Mel cells showed nuclear accumulation of beta-catenin and expression of the AXIN2 gene, and hence, constitutive activation of Wnt signaling. Mutational analysis identified a somatic heterozygous missense mutation in CTNNB1 exon three and a germline heterozygous deletion within AXIN2 exon seven in PR-Mel cells, and a somatic biallelic deletion within APC in MR-Mel cells. Deregulation of Wnt signaling and a defective MMR system were also present in the original tumor of PR and MR patients. Thus, we describe additional melanomas with mutations in CTNNB1 and APC, identify for the first time a germline AXIN2 mutation in a melanoma patient and suggest that inactivation of the MMR system and deregulation of the Wnt/beta-catenin signaling pathway cooperate to promote melanoma development and/or progression.
authors.affiliation: Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy. d.castiglia@idi.it
authors.forename: Daniele
authors.initials: D
authors.lastname: Castiglia
authors.forename: Silvia
authors.initials: S
authors.lastname: Bernardini
authors.forename: Ester
authors.initials: E
authors.lastname: Alvino
authors.forename: Elena
authors.initials: E
authors.lastname: Pagani
authors.forename: Naomi
authors.initials: N
authors.lastname: De Luca
authors.forename: Sabrina
authors.initials: S
authors.lastname: Falcinelli
authors.forename: Alberto
authors.initials: A
authors.lastname: Pacchiarotti
authors.forename: Enzo
authors.initials: E
authors.lastname: Bonmassar
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zambruno
authors.forename: Stefania
authors.initials: S
authors.lastname: D'Atri
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics* / Q000378:metabolism; D060466:Axin Protein; D015152:Blotting, Northern; D015153:Blotting, Western; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D053843:DNA Mismatch Repair; D045643:DNA Repair Enzymes / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments; D016133:Polymerase Chain Reaction; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: C491761:AXIN2 protein, human; D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D010446:Peptide Fragments; D051153:Wnt Proteins; D051176:beta Catenin; D045643:DNA Repair Enzymes