High prevalence of BRAF V600E mutations in Korean patients with ameloblastoma: Clinicopathological significance and correlation with epithelial‐mesenchymal transition

Abstract

Background BRAF V600E mutations are activating mutations that have recently been detected in ameloblastoma. However, their prevalence has not been reported in East Asian patients with ameloblastoma and their clinicopathological significance remains unclear. In this study, we examined the prevalence and clinicopathological significance of BRAF V600E mutations in Korean patients with ameloblastoma. In addition, we investigated the relationship between BRAF V600E mutations and epithelial‐mesenchymal transition, which has not been studied in ameloblastoma. Methods Thirty ameloblastoma tissue samples were collected, and DNA isolation, polymerase chain reaction, and Sanger sequencing were performed to detect BRAF V600E mutations. Immunohistochemistry was carried out using antibodies against two epithelial‐mesenchymal transition‐inducing transcription factors, Twist and Snail. Associations of BRAF V600E mutations with clinicopathological factors and expression of Twist and Snail were statistically analyzed. Results We found a high frequency (90.0%) of BRAF V600E mutations, and mutation status was not associated with clinicopathological factors including age, tumor location, and recurrence. Positive expression of Twist and Snail was observed in 33.3% and 56.7% of cases, respectively, and associated with recurrence (P = 0.020 and 0.010, respectively). There was no correlation between BRAF V600E mutation status and expression of Twist and Snail (P = 1.000, for both). Conclusions A higher prevalence of BRAF V600E mutations was identified in Korean patients with ameloblastoma compared with previous studies, which indicates that BRAF‐targeted therapies can be widely used for refractory ameloblastomas. Furthermore, our findings suggest that BRAF V600E mutations and epithelial‐mesenchymal transition may act independently in the development of ameloblastoma.

An immunohistochemical and genetic study of BRAFV600E mutation in Japanese patients with ameloblastoma

“…In our study, 97% of ameloblastomas—all but one case—occurred in the mandible. The BRAF V600E mutation is most common genetic alteration in ameloblastoma, and its frequency varied from 43% to 90% in previous studies 12–20 . Mutation of SMO is also seen in 82% of maxillary ameloblastoma; it is most common genetic event in ameloblastomas that develop in the maxilla 12 .…”

“…reported that 47% of ameloblastoma was IHC‐positive for BRAF V600E antibody. When BRAF V600E IHC expression and BRAF gene mutations were compared, 63%, 19 66% 13 and 73 % 14 of IHC‐positive cases reportedly had BRAF mutations. In our study, 69% (22/32) of total ameloblastoma cases showed positive BRAF V600E IHC staining, and 73% (16/22) of the positive cases had BRAF mutations.…”

“…BRAF is the most potent activator of the MARK pathway 11 . The BRAF V600E mutation is reportedly present in 43–90% of ameloblastomas 12–20 . However, its frequency seems to vary among tested geographic or racial groups, and no report of the BRAF mutation in Japanese patients with ameloblastoma is available.…”

Discrepancy between immunohistochemistry and sequencing for BRAF V600E in odontogenic tumours: Comparative analysis of two VE1 antibodies

“…The BRAF V600E mutation is the most common oncogenic mutation in the BRAF gene, which induces constitutive activation of the mitogen‐activated protein kinase (MAPK) pathway. BRAF V600E mutations are frequently found in melanoma, 1 thyroid cancer, 2 and colorectal cancer 3 and have also been detected in ameloblastoma, a clinically significant and locally invasive odontogenic tumour, through the use of molecular tests 4‐9 . Other odontogenic tumours presenting with ameloblastic epithelium, including ameloblastic carcinoma (AC), ameloblastic fibroma (AF), ameloblastic fibro‐odontoma (AFO), ameloblastic fibro‐dentinoma (AFD) and ameloblastic fibrosarcoma (AFS), have been reported to have the mutation 4‐6,10 …”

Expression of stem cell markers in stroma of odontogenic cysts and tumors

“…An additional level of action of SOX2 is promotion of tumor aggressiveness and the process of epithelial‑mesenchymal transition (EMT) in several types of cancers, like in tongue squamous cell carcinoma 27 . Initial evidence for occurrence of EMT in AMB 28,29 and also in OKC 30 has been reported; however, the involvement of SOX2 in this setting remains to be clarified and related to the differential expression that we have found between the stroma of odontogenic tumors and cysts. Therapeutically, several strategies that have recently been described targeting SOX2, 31 further justify this investigation.…”