Wong Kim, Bishop Justin A, Weinreb Ilan, Motta Marialetizia, Del Castillo Velasco-Herrera Martin, Bellacchio Emanuele, Ferreira Ingrid, van der Weyden Louise, Boccacino Jacqueline M, Lauri Antonella, Rotundo Giovannina, Ciolfi Andrea, Cheema Saamin, Olvera-León Rebeca, Offord Victoria, Droop Alastair, Vermes Ian, Allgäuer Michael, Hyrcza Martin, Anderson Elizabeth, Smith Katie, de Saint Aubain Nicolas, Mogler Carolin, Stenzinger Albrecht, Arends Mark J, Brenn Thomas, Tartaglia Marco, Adams David J
Experimental Cancer Genetics, Wellcome Sanger Institute, Hinxton, Cambridge, UK.
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Nat Commun. 2025 May 19;16(1):4657. doi: 10.1038/s41467-025-59871-3.
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.
涎腺基底细胞腺瘤（BCA）和基底细胞腺癌（BCAC）是罕见肿瘤，很难相互区分以及与其他涎腺肿瘤亚型区分开来。通过新一代测序，我们在BCA中鉴定出一种反复出现的FBXW11错义突变（p.F517S），该突变与先前报道的CTNNB1 p.I35T功能获得性（GoF）突变相互排斥，这些突变共同占BCA的94%。在体外，突变型FBXW11的特征是与β-连环蛋白的结合缺陷以及细胞核内较高的蛋白质水平。这与β-连环蛋白核表达增加和Wnt/β-连环蛋白通路激活一致。BCAC的基因组图谱与BCA不同，具有热点DICER1和HRAS突变以及影响PI3K/AKT和NF-κB信号通路基因的推定驱动突变。这些发现对BCA和BCAC的诊断和治疗具有重要意义，尽管它们在组织病理学上有重叠，但可能是不相关的实体。
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