title: Activating FGFR2-RAS-BRAF mutations in ameloblastoma.
abstract: OBJECTIVE
  Ameloblastoma is an odontogenic neoplasm whose overall mutational landscape has not been well characterized. We sought to characterize pathogenic mutations in ameloblastoma and their clinical and functional significance with an emphasis on the mitogen-activated protein kinase (MAPK) pathway.
  
  
  METHODS
  A total of 84 ameloblastomas and 40 non-ameloblastoma odontogenic tumors were evaluated with a combination of BRAF V600E allele-specific PCR, VE1 immunohistochemistry, the Ion AmpliSeq Cancer Hotspot Panel, and Sanger sequencing. Efficacy of a BRAF inhibitor was evaluated in an ameloblastoma-derived cell line.
  
  
  RESULTS
  Somatic, activating, and mutually exclusive RAS-BRAF and FGFR2 mutations were identified in 88% of cases. Somatic mutations in SMO, CTNNB1, PIK3CA, and SMARCB1 were also identified. BRAF V600E was the most common mutation, found in 62% of ameloblastomas and in ameloblastic fibromas/fibrodentinomas but not in other odontogenic tumors. This mutation was associated with a younger age of onset, whereas BRAF wild-type cases arose more frequently in the maxilla and showed earlier recurrences. One hundred percent concordance was observed between VE1 immunohistochemistry and molecular detection of BRAF V600E mutations. Ameloblastoma cells demonstrated constitutive MAPK pathway activation in vitro. Proliferation and MAPK activation were potently inhibited by the BRAF inhibitor vemurafenib.
  
  
  CONCLUSIONS
  Our findings suggest that activating FGFR2-RAS-BRAF mutations play a critical role in the pathogenesis of most cases of ameloblastoma. Somatic mutations in SMO, CTNNB1, PIK3CA, and SMARCB1 may function as secondary mutations. BRAF V600E mutations have both diagnostic and prognostic implications. In vitro response of ameloblastoma to a BRAF inhibitor suggests a potential role for targeted therapy.
authors.affiliation: Departments of Pathology and.
authors.forename: Noah A
authors.initials: NA
authors.lastname: Brown
authors.affiliation: Departments of Pathology and.
authors.forename: Delphine
authors.initials: D
authors.lastname: Rolland
authors.affiliation: Departments of Pathology and.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: McHugh
authors.affiliation: Departments of Pathology and.
authors.forename: Helmut C
authors.initials: HC
authors.lastname: Weigelin
authors.affiliation: Biostatistics, University of Michigan, Ann Arbor, Michigan.
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.affiliation: Departments of Pathology and.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Lim
authors.affiliation: Departments of Pathology and.
authors.forename: Kojo S J
authors.initials: KS
authors.lastname: Elenitoba-Johnson
authors.affiliation: Departments of Pathology and bbetz@med.umich.edu.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Betz
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000564:Ameloblastoma / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics; D045744:Cell Line, Tumor; D002648:Child; D005260:Female; D006801:Humans; D007573:Jaw Neoplasms / Q000235:genetics*; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C496353:FGFR2 protein, human; D051497:Receptor, Fibroblast Growth Factor, Type 2; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins