Wnt/β-catenin activation by mutually exclusive FBXW11 and CTNNB1 hotspot mutations drives salivary basal cell adenoma
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.
Authors
- Emanuele Bellacchio (ORCID: https://orcid.org/0000-0002-2757-849X)
- Thomas Brenn (ORCID: https://orcid.org/0000-0002-0089-0352)
- Saamin Cheema (ORCID: https://orcid.org/0000-0002-5297-2042)
- Martin Hyrcza
- Mark J. Arends (ORCID: https://orcid.org/0000-0002-6826-8770)
- Ian Vermes
- Martin Del Castillo Velasco‐Herrera (ORCID: https://orcid.org/0000-0001-5956-0211)
- Louise van der Weyden (ORCID: https://orcid.org/0000-0002-0645-1879)
- Albrecht Stenzinger (ORCID: https://orcid.org/0000-0003-1001-103X)
- Antonella Lauri (ORCID: https://orcid.org/0000-0003-2260-182X)
- Victoria Offord (ORCID: https://orcid.org/0000-0003-3104-317X)
- Ingrid Ferreira (ORCID: https://orcid.org/0000-0002-4321-5250)
- Katherine A. Smith (ORCID: https://orcid.org/0000-0001-8150-5702)
- Jacqueline Marcia Boccacino (ORCID: https://orcid.org/0000-0001-6813-5217)
- Marco Tartaglia (ORCID: https://orcid.org/0000-0001-7736-9672)
- Nicolas de Saint Aubain
- Andrea Ciolfi (ORCID: https://orcid.org/0000-0002-6191-0978)
- Kim Wong (ORCID: https://orcid.org/0000-0002-0984-1477)
- Justin A. Bishop (ORCID: https://orcid.org/0000-0002-0412-6810)
- Marialetizia Motta (ORCID: https://orcid.org/0000-0001-6592-910X)
- Carolin Mogler (ORCID: https://orcid.org/0000-0003-3400-7254)
- Giovannina Rotundo (ORCID: https://orcid.org/0000-0002-9163-7781)
- Alastair Droop (ORCID: https://orcid.org/0000-0001-7695-7480)
- Michael Allgäeuer (ORCID: https://orcid.org/0000-0003-4518-7887)
- David J. Adams (ORCID: https://orcid.org/0000-0001-9490-0306)
- Elizabeth Anderson
- Rebeca Olvera-León
- Ilan Weinreb
Institutions
- Université Libre de Bruxelles (BE)
- University Health Network (CA)
- University of Toronto (CA)
- Heidelberg University (DE)
- University of Michigan (US)
- Toronto General Hospital (CA)
- University Hospital Heidelberg (DE)
- Wellcome Sanger Institute (GB)
- Edinburgh Cancer Research (GB)
- Institute of Cancer Research (CA)
- Bambino Gesù Children's Hospital (IT)
- Technical University of Munich (DE)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-19
- DOI
- https://doi.org/10.1038/s41467-025-59871-3
- Citations
- 6
- Primary Topic
- Salivary Gland Tumors Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 12.04
Funders
- Wellcome
- Wellcome Trust
- Ministero della Salute
- Associazione Italiana per la Ricerca sul Cancro
- Medical Research Council