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Nat Genet. 2014 Jul;46(7):722-5. doi: 10.1038/ng.2986. Epub 2014 May 25.

Identification of recurrent SMO and BRAF mutations in ameloblastomas.

Author information

  • 11] Department of Pathology, Stanford University, Stanford, California, USA. [2].
  • 21] Department of Biochemistry, Stanford University, Stanford, California, USA. [2] Department of Developmental Biology, Stanford University, Stanford, California, USA. [3] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA. [4] Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA. [5].
  • 31] Department of Biochemistry, Stanford University, Stanford, California, USA. [2] Department of Developmental Biology, Stanford University, Stanford, California, USA. [3] Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA. [4] Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA.
  • 41] Genomic Health, Redwood City, California, USA. [2].
  • 5Genomic Health, Redwood City, California, USA.
  • 6Department of Pathology, Stanford University, Stanford, California, USA.
  • 7Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
  • 8Department of Biochemistry, Akita University Graduate School of Medicine, Akita, Japan.
  • 9Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio, USA.
  • 10Department of Pathology, Oregon Health and Sciences University, Portland, Oregon, USA.

Erratum in

  • Nat Genet. 2015 Jan;47(1):97.

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.

PMID:
24859340
[PubMed - indexed for MEDLINE]
PMCID:
PMC4418232
Free PMC Article
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