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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Identification of recurrent SMO and BRAF mutations in ameloblastomas
Robert T Sweeney1, Andrew C McClary1, Benjamin R Myers2
11] Department of Pathology, Stanford University, Stanford, California, USA. [2].
Abstract:
Here we report the discovery of oncogenic mutations in the Hedgehog and mitogen-activated protein kinase (MAPK) pathways in over 80% of ameloblastomas, locally destructive odontogenic tumors of the jaw, by genomic analysis of archival material. Mutations in SMO (encoding Smoothened, SMO) are common in ameloblastomas of the maxilla, whereas BRAF mutations are predominant in tumors of the mandible. We show that a frequently occurring SMO alteration encoding p.Leu412Phe is an activating mutation and that its effect on Hedgehog-pathway activity can be inhibited by arsenic trioxide (ATO), an anti-leukemia drug approved by the US Food and Drug Administration (FDA) that is currently in clinical trials for its Hedgehog-inhibitory activity. In a similar manner, ameloblastoma cells harboring an activating BRAF mutation encoding p.Val600Glu are sensitive to the BRAF inhibitor vemurafenib. Our findings establish a new paradigm for the diagnostic classification and treatment of ameloblastomas.
Insights
Oncogenic mutations in Hedgehog and MAPK pathways are found in over 80% of ameloblastomas. Targeted therapies like arsenic trioxide and vemurafenib show promise for treating these jaw tumors.
Area of Science:
- Oncology
- Genetics
- Oral Pathology
Background:
- Ameloblastomas are locally destructive odontogenic tumors of the jaw.
- Understanding the molecular drivers of ameloblastoma is crucial for developing targeted therapies.
Purpose of the Study:
- To identify oncogenic mutations in the Hedgehog and mitogen-activated protein kinase (MAPK) pathways in ameloblastomas.
- To investigate the therapeutic potential of targeting these identified pathways.
Main Methods:
- Genomic analysis of archival ameloblastoma tissue samples.
- Functional assays to confirm the oncogenic nature of identified mutations.
- In vitro drug sensitivity testing using targeted inhibitors.
Main Results:
- Over 80% of ameloblastomas harbor mutations in the Hedgehog and MAPK pathways.
- SMO mutations (e.g., p.Leu412Phe) are common in maxillary ameloblastomas and activate the Hedgehog pathway.
- BRAF mutations (e.g., p.Val600Glu) are predominant in mandibular ameloblastomas.
- Arsenic trioxide (ATO) inhibits Hedgehog pathway activity driven by SMO mutations.
- Vemurafenib effectively targets ameloblastoma cells with activating BRAF mutations.
Conclusions:
- Oncogenic mutations in Hedgehog and MAPK pathways are key drivers of ameloblastoma development.
- Targeting SMO with ATO and BRAF with vemurafenib represents a promising therapeutic strategy for ameloblastomas.
- These findings establish a new framework for classifying and treating ameloblastomas based on their molecular profile.
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