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Published on: August 15, 2019
Identification of CTNNB1 mutations, CTNNB1 amplifications, and an Axin2 splice variant in juvenile angiofibromas
Silke Wemmert1, Vivienne Willnecker2, Philipp Kulas2
1Department of Otolaryngology, Saarland University Medical Center, 66421, Homburg/Saar, Germany. silke.wemmert@uks.eu.
Abstract:
Juvenile angiofibromas (JAs) are benign fibro-vascular tumors occurring nearly exclusively in adolescent males. Even less is known about this rare tumor entity, alterations affecting the Wnt-pathway seem to play a pivotal role in tumor biology as activating CTNNB1 mutations have been detected. However, the knowledge of Wnt-pathway changes is still limited. Therefore, we aimed to determine in JAs further insight into Wnt/β-catenin pathway components. In our present study, genetic alterations of the Wnt-pathway members CTNNB1, APC, GSK3β, and Axin2 detected by metaphase comparative genomic hybridization (CGH) were shown to result in elevated transcript levels in the majority of JA samples compared to nasal mucosa stroma (p < 0.001, p = 0.001, p = 0.046, and p = 0.006, respectively). Additionally, amplifications of CTNNB1 were validated by fluorescence in situ hybridization (FISH) and genomic qPCR. Moreover, our mutation analysis detected already known mutations as well as, to the best of our knowledge, mutations and an interstitial deletion of CTNNB1 not described in JAs before. Additionally, a so far unknown transcribed Axin2 splice variant was found, but no further Axin2 mutations. Taken together, our current study supports the importance of aberrant Wnt-signaling as a common event in JAs, most likely by the observed genetic alterations driven by mutations, interstitial deletions but also amplifications of CTNNB1 contributing to the stabilization of β-catenin.
Insights
Juvenile angiofibromas (JAs) involve Wnt/β-catenin pathway alterations. Genetic changes in CTNNB1 and other Wnt-pathway genes drive JA development, highlighting Wnt-signaling
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Juvenile angiofibromas (JAs) are rare, benign fibro-vascular tumors predominantly affecting adolescent males.
- Aberrant Wnt-pathway signaling, particularly CTNNB1 mutations, is implicated in JA tumorigenesis.
- Comprehensive understanding of Wnt-pathway alterations in JAs remains limited.
Purpose of the Study:
- To investigate genetic alterations and transcript levels of Wnt-pathway components in JAs.
- To identify novel mutations and genetic events within the Wnt-pathway in this tumor type.
- To elucidate the role of Wnt/β-catenin signaling in the pathogenesis of JAs.
Main Methods:
- Metaphase comparative genomic hybridization (CGH) was employed to detect genetic alterations in Wnt-pathway genes (CTNNB1, APC, GSK3β, Axin2).
- Transcript levels of these genes were quantified and compared to nasal mucosa stroma.
- Fluorescence in situ hybridization (FISH) and genomic quantitative PCR (qPCR) were used to validate CTNNB1 amplifications.
- Mutation analysis was performed to identify genetic variations in CTNNB1 and Axin2.
Main Results:
- Significant elevations in transcript levels of CTNNB1, APC, GSK3β, and Axin2 were observed in JAs compared to nasal mucosa stroma (p < 0.001 to p = 0.046).
- CTNNB1 amplifications were confirmed by FISH and genomic qPCR.
- Novel mutations and an interstitial deletion in CTNNB1, along with a previously undescribed transcribed Axin2 splice variant, were identified in JAs.
- No additional Axin2 mutations were found.
Conclusions:
- Aberrant Wnt-signaling is a common and crucial event in the development of JAs.
- Genetic alterations, including mutations, interstitial deletions, and amplifications of CTNNB1, contribute to β-catenin stabilization.
- These findings deepen the understanding of Wnt-pathway dysregulation in JAs and suggest potential therapeutic targets.
