Recurrent CTNNB1 mutations in craniofacial osteomas

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

doi:10.1038/s41379-021-00956-x

Daniel Baumhoer, Ruth Berthold + Show 11 more

Open Access

https://doi.org/10.1038/s41379-021-00956-x

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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.

Highlights

Osteoma is a benign bone forming tumor arising predominantly on the surface of bones formed by membranous ossification, i.e., the craniofacial, and jaw bones [1]
Given well-known examples of neoplasms arising in the setting of FAP that occur independently from adenomatous polyposis coli (APC) mutations in the sporadic setting and the established role of WNT/β-catenin signaling in osteogenesis, we set out to analyze a cohort of craniofacial osteomas for the presence of CTNNB1 gene mutations
The aetiology of osteomas is an ongoing matter of debate

Summary

Introduction

Osteoma is a benign bone forming tumor arising predominantly on the surface of bones formed by membranous ossification, i.e., the craniofacial, and jaw bones [1]. While their prevalence has been reported to reach 6.4% in selected series [2], the true incidence of osteomas is unknown, and it seems likely that many lesions remain clinically undetected due to the lack of specific symptoms. Osteoma is rarely associated with Gardner syndrome (representing a phenotypic variant of familial adenomatous polyposis (FAP)), characterized by APC mutations and aberrant activation of WNT/β-catenin signaling [5, 6]. Given well-known examples of neoplasms arising in the setting of FAP (e.g., desmoid fibromatosis, hepatoblastoma) that occur independently from APC mutations in the sporadic setting and the established role of WNT/β-catenin signaling in osteogenesis (reviewed in [8, 9]), we set out to analyze a cohort of craniofacial osteomas for the presence of CTNNB1 gene mutations

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