1. Recurrent CTNNB1 mutations in craniofacial osteomas
- Author
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Ilka Isfort, Lorena Heinst, Daniel Baumhoer, Florian M. Thieringer, Jan Sperveslage, Baptiste Ameline, Marcel Trautmann, Claudia Rudack, Volker Vieth, Inga Grünewald, Wolfgang Hartmann, Eva Wardelmann, and Ruth Berthold
- Subjects
Pathology ,medicine.medical_specialty ,Mutation ,Wnt signaling pathway ,Biology ,medicine.disease ,medicine.disease_cause ,Phenotype ,Pathology and Forensic Medicine ,Familial adenomatous polyposis ,body regions ,Gene expression profiling ,Gardner Syndrome ,medicine ,Craniofacial ,Osteoma - Abstract
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.
- Published
- 2022
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