• A Corrigendum to this article was published on 30 December 2014

This article has been updated


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.

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Change history

  • 12 November 2014

    In the version of this article initially published, the introductory paragraph mistakenly stated that ameloblasts were "cells in the tooth roots of the upper (maxilla) and lower (mandible) jaw responsible for depositing enamel during tooth development (odontogenesis)." The correct location for human ameloblasts is in the developing tooth. Ameloblasts are the normal cell type that ameloblastoma cells resemble and are responsible for forming the enamel covering on tooth crowns. The error has been corrected in the HTML and PDF versions of the article.


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We would like to thank E. Epstein for assistance. We would like to thank C. Millward, H. Kaplan and M. Labusch for histology and pathology support. We are also grateful to H. Harada (Iwate Medical University) for sharing the AM-1 cell line.

Author information

Author notes

    • Kevin A Kwei

    Present address: Onyx Pharmaceuticals, South San Francisco, California, USA.

    • Robert T Sweeney
    • , Andrew C McClary
    • , Benjamin R Myers
    •  & Jewison Biscocho

    These authors contributed equally to this work.


  1. Department of Pathology, Stanford University, Stanford, California, USA.

    • Robert T Sweeney
    • , Andrew C McClary
    • , Jewison Biscocho
    • , Xue Gong
    • , Carol D Jones
    • , Sushama Varma
    • , Justin I Odegaard
    • , James L Zehnder
    • , Jonathan R Pollack
    •  & Robert B West
  2. Department of Biochemistry, Stanford University, Stanford, California, USA.

    • Benjamin R Myers
    • , Lila Neahring
    •  & Philip A Beachy
  3. Department of Developmental Biology, Stanford University, Stanford, California, USA.

    • Benjamin R Myers
    • , Lila Neahring
    •  & Philip A Beachy
  4. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA.

    • Benjamin R Myers
    • , Lila Neahring
    •  & Philip A Beachy
  5. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA.

    • Benjamin R Myers
    • , Lila Neahring
    •  & Philip A Beachy
  6. Genomic Health, Redwood City, California, USA.

    • Kevin A Kwei
    • , Kunbin Qu
    •  & Robert J Pelham
  7. Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

    • Tony Ng
  8. Department of Biochemistry, Akita University Graduate School of Medicine, Akita, Japan.

    • Toshihiro Sugiyama
    •  & Souichi Koyota
  9. Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio, USA.

    • Brian P Rubin
  10. Department of Pathology, Oregon Health and Sciences University, Portland, Oregon, USA.

    • Megan L Troxell


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R.T.S., A.C.M., J.R.P. and R.B.W. designed the study and wrote the manuscript. A.C.M., B.R.M., J.R.P. and R.B.W. designed the figures. R.T.S., X.G., J.R.P. and R.B.W. analyzed raw sequence data. J.B. and J.R.P. performed mutation validation (PCR and Sanger sequencing). B.R.M., L.N., J.B., J.R.P. and P.A.B. designed and implemented functional studies. C.D.J., J.I.O. and J.L.Z. performed targeted sequencing (TruSeq). K.A.K., K.Q. and R.J.P. performed transcriptome sequencing. S.V. performed immunohistochemistry. T.N., B.P.R. and M.L.T. provided cases for evaluation. T.S. and S.K. provided key cell line reagents.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Philip A Beachy or Jonathan R Pollack or Robert B West.

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    Clinical features and mutation status of cases.

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