Genetic study of the BRAF gene reveals new variants and high frequency of the V600E mutation among Iranian ameloblastoma patients

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Ameloblastoma is a benign, slow‐growing and locally invasive tumor. It is one of the most prevalent odontogenic tumors with an incidence rate of 1% of all oral tumors and approximately 18% of odontogenic tumors. It is able to perforate the cortical bone of the jaw to cause facial asymmetry.1 Ameloblastoma is known to originate from the remaining tooth lamina and to reduce enamel epithelium, epithelial cell rests of Malassez, or the basal layer cells. It often affects the mandible (80%‐85% of cases).2 Ameloblastomas are categorized into unicystic, multicystic (solid), peripheral, and malignant subtypes. The conventional solid or multicystic subtype, with an incidence of 86% of cases, is more infiltrative with a higher rate of recurrence.1 Their histological variations consist of follicular, plexiform, acanthomatous, granular cell, basal cell, and desmoplastic types, among which the follicular and plexiform types are the most common types.4
A group of genes have been investigated in patients with ameloblastoma. However, further investigations are required to detect the mechanisms of oncogenesis and molecular pathogenesis. Mutations influencing several genes within the MAPK pathway are currently known to occur in a large number of cases. The biological importance of these mutations is pronounced by their high frequency and pattern of mutual exclusivity. The hedgehog and FGFR‐MAPK pathway components have been reported to be expressed during tooth development and in ameloblastomas.5 Moreover, analysis using gene expression microarrays, immunohistochemistry, and quantitative RT‐PCR have, in particular, indicated the differential expression of Hedgehog pathway genes in ameloblastomas.8
Both in vitro and anecdotal clinical data suggest MAPK pathway inhibition as a promising treatment option for ameloblastoma.10 Variable sensitivity of primary ameloblastoma cells to EGFR‐targeted drugs in vitro has been reported.9 The BRAF V600E mutation (15 of 24 samples, 63%) was found in the cell line overexpressing EGFR but resistant to EGFR inhibition. These data provide a novel insight into the poorly recognized molecular pathogenesis of ameloblastoma and offer a rationale for testing the drugs targeting EGFR or mutant BRAF as novel therapies for ameloblastoma.9
More than 40 different mutations have been reported in the BRAF gene related to human cancer.11 Interestingly, the BRAF V600E mutation has been implicated as the most common mutation (90% of all BRAF mutations) in ameloblastoma resulting in constitutive activation of the gene.12 The presence or absence of this mutation has been associated with several clinicopathological properties, including location, age at diagnosis, histology, and prognosis.10
Although there are several studies to address the prevalence of the BRAF V600E mutation in ameloblastoma patients,5 they do show that the mutation frequency differs in different populations; Iran is a big country with a population about 80 million people. However, there is no report on the role of BRAF in ameloblastoma. Therefore, the current research was launched to study the BRAF V600E mutation among a cohort of Iranian patients with ameloblastoma.
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