Recurrent CTNNB1 mutations in craniofacial osteomas.

Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 2022 Apr

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Osteoma is a benign bone forming tumor predominantly arising on the surface of craniofacial bones. While the vast majority of osteomas develops sporadically, a small subset of cases is associated with Gardner syndrome, a phenotypic variant of familial adenomatous polyposis caused by mutations in the APC gene resulting in aberrant activation of WNT/β-catenin signaling. In a sequencing analysis on a cohort of sporadic, non-syndromal osteomas, we identified hotspot mutations in the CTNNB1 gene (encoding β-catenin) in 22 of 36 cases (61.1%), harbouring allelic frequencies ranging from 0.04 to 0.53, with the known S45P variant representing the most frequent alteration. Based on NanoString multiplex expression profiling performed in a subset of cases, CTNNB1-mutated osteomas segregated in a defined "WNT-cluster", substantiating functionality of CTNNB1 mutations which are associated with β-catenin stabilization. Our findings for the first time convincingly show that osteomas represent genetically-driven neoplasms and provide evidence that aberrant WNT/β-catenin signaling plays a fundamental role in their pathogenesis, in line with the well-known function of WNT/β-catenin in osteogenesis. Our study contributes to a better understanding of the molecular pathogenesis underlying osteoma development and establishes a helpful diagnostic molecular marker for morphologically challenging cases. © 2021. The Author(s).

Citation

Daniel Baumhoer, Ruth Berthold, Ilka Isfort, Lorena Heinst, Baptiste Ameline, Inga Grünewald, Florian M Thieringer, Claudia Rudack, Eva Wardelmann, Volker Vieth, Jan Sperveslage, Marcel Trautmann, Wolfgang Hartmann. Recurrent CTNNB1 mutations in craniofacial osteomas. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2022 Apr;35(4):489-494