title: High frequency of BRAF V600E mutations in ameloblastoma.
abstract: Ameloblastoma is a benign but locally infiltrative odontogenic neoplasm. Although ameloblastomas rarely metastasise, recurrences together with radical surgery often result in facial deformity and significant morbidity. Development of non-invasive therapies has been precluded by a lack of understanding of the molecular background of ameloblastoma pathogenesis. When addressing the role of ERBB receptors as potential new targets for ameloblastoma, we discovered significant EGFR over-expression in clinical samples using real-time RT-PCR, but observed variable sensitivity of novel primary ameloblastoma cells to EGFR-targeted drugs in vitro. In the quest for mutations downstream of EGFR that could explain this apparent discrepancy, Sanger sequencing revealed an oncogenic BRAF V600E mutation in the cell line resistant to EGFR inhibition. Further analysis of the clinical samples by Sanger sequencing and BRAF V600E-specific immunohistochemistry demonstrated a high frequency of BRAF V600E mutations (15 of 24 samples, 63%). These data provide novel insight into the poorly understood molecular pathogenesis of ameloblastoma and offer a rationale to test drugs targeting EGFR or mutant BRAF as novel therapies for ameloblastoma.
authors.affiliation: Department of Medical Biochemistry and Genetics and MediCity Research Laboratories, University of Turku, Finland; Turku Doctoral Programme of Molecular Medicine, Turku, Finland.
authors.forename: Kari J
authors.initials: KJ
authors.lastname: Kurppa
authors.forename: Javier
authors.initials: J
authors.lastname: Catón
authors.forename: Peter R
authors.initials: PR
authors.lastname: Morgan
authors.forename: Ari
authors.initials: A
authors.lastname: Ristimäki
authors.forename: Blandine
authors.initials: B
authors.lastname: Ruhin
authors.forename: Jari
authors.initials: J
authors.lastname: Kellokoski
authors.forename: Klaus
authors.initials: K
authors.lastname: Elenius
authors.forename: Kristiina
authors.initials: K
authors.lastname: Heikinheimo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000564:Ameloblastoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007573:Jaw Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D018579:Patient Selection; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D066247:Receptor, ErbB-4; D015398:Signal Transduction / Q000187:drug effects; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF; EGFR; ameloblastoma; odontogenic tumour; oncogenic mutation; targeted therapy