Wnt/β-catenin activation by mutually exclusive FBXW11 and CTNNB1 hotspot mutations drives salivary basal cell adenoma

Kim Wong, Justin A. Bishop, Ilan Weinreb, Marialetizia Motta, Martin Del Castillo Velasco-Herrera, Emanuele Bellacchio, Ingrid Ferreira, Louise van der Weyden, Jacqueline M. Boccacino, Antonella Lauri, Giovannina Rotundo, Andrea Ciolfi, Saamin Cheema, Rebeca Olvera-León, Victoria Offord, Alastair Droop, Ian Vermes, Michael Allgäuer, Martin Hyrcza, Elizabeth Anderson, Katie Smith, Nicolas de Saint Aubain, Carolin Mogler, Albrecht Stenzinger, Mark J. Arends, Thomas Brenn, Marco Tartaglia and David J. Adams ()
Additional contact information
Kim Wong: Wellcome Sanger Institute
Justin A. Bishop: University of Texas Southwestern Medical Center
Ilan Weinreb: Toronto General Hospital
Marialetizia Motta: IRCCS
Martin Del Castillo Velasco-Herrera: Wellcome Sanger Institute
Emanuele Bellacchio: IRCCS
Ingrid Ferreira: Wellcome Sanger Institute
Louise van der Weyden: Wellcome Sanger Institute
Jacqueline M. Boccacino: Wellcome Sanger Institute
Antonella Lauri: IRCCS
Giovannina Rotundo: IRCCS
Andrea Ciolfi: IRCCS
Saamin Cheema: Wellcome Sanger Institute
Rebeca Olvera-León: Wellcome Sanger Institute
Victoria Offord: Wellcome Sanger Institute
Alastair Droop: Wellcome Sanger Institute
Ian Vermes: Wellcome Sanger Institute
Michael Allgäuer: University Hospital Heidelberg
Martin Hyrcza: Arnie Charboneau Cancer Institute
Elizabeth Anderson: Wellcome Sanger Institute
Katie Smith: Wellcome Sanger Institute
Nicolas de Saint Aubain: Université Libre de Bruxelles
Carolin Mogler: Technical University Munich
Albrecht Stenzinger: University Hospital Heidelberg
Mark J. Arends: Institute of Genetics and Cancer
Thomas Brenn: University of Michigan
Marco Tartaglia: IRCCS
David J. Adams: Wellcome Sanger Institute

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Basal cell adenoma (BCA) and basal cell adenocarcinoma (BCAC) of the salivary gland are rare tumours that can be difficult to distinguish from each other and other salivary gland tumour subtypes. Using next-generation sequencing, we identify a recurrent FBXW11 missense mutation (p.F517S) in BCA that is mutually exclusive with the previously reported CTNNB1 p.I35T gain-of-function (GoF) mutation with these mutations collectively accounting for 94% of BCAs. In vitro, mutant FBXW11 is characterised by defective binding to β-catenin and higher protein levels within the nucleus. This is consistent with the increased nuclear expression of β-catenin and activation of the Wnt/β-catenin pathway. The genomic profiles of BCAC are distinct from BCA, with hotspot DICER1 and HRAS mutations and putative driver mutations affecting PI3K/AKT and NF-κB signalling pathway genes. These findings have important implications for the diagnosis and treatment of BCA and BCAC, which, despite histopathologic overlap, may be unrelated entities.

Date: 2025
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DOI: 10.1038/s41467-025-59871-3

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