Recurrent CTNNB1 mutations in craniofacial osteomas

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/beta-catenin signaling. In a sequencing analysis on a cohort of sporadic, non-syndromal osteomas, we identified hotspot mutations in the CTNNB1 gene (encoding beta-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 beta-catenin stabilization. Our findings for the first time convincingly show that osteomas represent genetically-driven neoplasms and provide evidence that aberrant WNT/beta-catenin signaling plays a fundamental role in their pathogenesis, in line with the well-known function of WNT/beta-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.

Automated summary

The study reveals that osteomas are genetically-driven neoplasms caused by mutations in the CTNNB1 gene and associated with aberrant activation of WNT/β-catenin signaling. It provides a better understanding of the molecular pathogenesis underlying osteoma development and establishes a diagnostic molecular marker for morphologically challenging cases.