title: Identification of recurrent SMO and BRAF mutations in ameloblastomas.
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.
authors.affiliation: 1] Department of Pathology, Stanford University, Stanford, California, USA. [2].
authors.forename: Robert T
authors.initials: RT
authors.lastname: Sweeney
authors.affiliation: 1] Department of Pathology, Stanford University, Stanford, California, USA. [2].
authors.forename: Andrew C
authors.initials: AC
authors.lastname: McClary
authors.affiliation: 1] 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].
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Myers
authors.affiliation: 1] Department of Pathology, Stanford University, Stanford, California, USA. [2].
authors.forename: Jewison
authors.initials: J
authors.lastname: Biscocho
authors.affiliation: 1] 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.
authors.forename: Lila
authors.identifier: 0000000322728732
authors.initials: L
authors.lastname: Neahring
authors.affiliation: 1] Genomic Health, Redwood City, California, USA. [2].
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Kwei
authors.affiliation: Genomic Health, Redwood City, California, USA.
authors.forename: Kunbin
authors.initials: K
authors.lastname: Qu
authors.affiliation: Department of Pathology, Stanford University, Stanford, California, USA.
authors.forename: Xue
authors.initials: X
authors.lastname: Gong
authors.affiliation: Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Tony
authors.initials: T
authors.lastname: Ng
authors.affiliation: Department of Pathology, Stanford University, Stanford, California, USA.
authors.forename: Carol D
authors.initials: CD
authors.lastname: Jones
authors.affiliation: Department of Pathology, Stanford University, Stanford, California, USA.
authors.forename: Sushama
authors.initials: S
authors.lastname: Varma
authors.affiliation: Department of Pathology, Stanford University, Stanford, California, USA.
authors.forename: Justin I
authors.initials: JI
authors.lastname: Odegaard
authors.affiliation: Department of Biochemistry, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Sugiyama
authors.affiliation: Department of Biochemistry, Akita University Graduate School of Medicine, Akita, Japan.
authors.forename: Souichi
authors.initials: S
authors.lastname: Koyota
authors.affiliation: Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Rubin
authors.affiliation: Department of Pathology, Oregon Health and Sciences University, Portland, Oregon, USA.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Troxell
authors.affiliation: Genomic Health, Redwood City, California, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Pelham
authors.affiliation: Department of Pathology, Stanford University, Stanford, California, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Zehnder
authors.affiliation: 1] 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.
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beachy
authors.affiliation: Department of Pathology, Stanford University, Stanford, California, USA.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Pollack
authors.affiliation: Department of Pathology, Stanford University, Stanford, California, USA.
authors.forename: Robert B
authors.initials: RB
authors.lastname: West
mesh_terms: D000564:Ameloblastoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D007573:Jaw Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D010087:Oxides / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D000072086:Smoothened Receptor; D013449:Sulfonamides / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D007211:Indoles; D010087:Oxides; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D013449:Sulfonamides; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000077237:Arsenic Trioxide