In addition, we investigated the relationship between BRAFV600E mutations and epithelial-mesenchymal transition, which has not been studied in ameloblastoma.
Expression of CKs was consistent with other histological variants of ameloblastoma (AM), but AM-BC had significantly higher p53 and Ki-67 (p < 0.05) labeling indices than other histological variants of AM.Two patients had BRAF gene mutations.
Most ameloblastomas (AM) in humans harbour mutually-exclusive driving mutations in BRAF, HRAS, KRAS, NRAS or FGFR2 that activate MAPK signalling, and in SMO that activates Hedgehog signalling.
While ameloblastomas show BRAFp.V600E mutations, adenomatoid odontogenic tumours harbour either KRAS p.G12R or p.G12 V. The lack of understanding of the core molecular changes involved in tumour initiation and progression represents a critical barrier to developing new strategies for cancer detection and prevention.
BRAFV600E mutation is common in mandibular ameloblastomas, especially in cases of tumours larger than 4 cm and in the posterior region of the mandible.
<b>Conclusions:</b> The complete response observed here illustrate the role of molecular profiling in complicate clinical situation of rare head and neck cancer and the potential benefit of BRAF-targeted therapy in ameloblastoma carrying <i>BRAF</i> V600E mutation.
The presence of BRAF-V600E mutations in ameloblastoma was related to decreased levels of glycerol in comparison with tumors carrying only wild-type alleles of this gene.
High-throughput DNA sequencing methods, such as next-generation sequencing using Illumina have yielded advancements in studies on MAPK signaling pathways and their association with AM; in particular, BRAFV600E is mediated by the activation of the Ras/Raf/MAPK pathway.
In conclusion, mutation profiles of BRAF wild-type craniopharyngiomas and ameloblastomas share mutations of FGFR genes and have additional mutations with potential for targeted therapy.
Our data suggest that ameloblastomas harboring single BRAF mutations are excellent candidates for neo-adjuvant therapies with combined BRAF/MEK inhibitors and that the risk of recurrence maybe stratified based on the mutational spectrum.
Although recent identification of BRAFV600E mutation and subsequent activation of mitogen-activated protein kinase (MAPK) pathway in ameloblastoma and odontogenic tumors provide additional options with targeted therapeutics, the molecular background of OKC is not well understood.
Furthermore, ghost cells were present in two cases of ameloblastoma with BRAF and CTNNB1 mutations, indicating that ghost cells form due to mutations in CTNNB1.
Specific candidate genes have been sequenced in odontogenic lesions, revealing recurrent BRAF mutation in the case of ameloblastoma, KRAS mutation in adenomatoid odontogenic tumours, PTCH1 mutation in odontogenic keratocysts, and CTNNB1 (Beta-catenin) mutation in calcifying odontogenic cysts.
That this therapy was not effective in another primary cell culture led to the discovery of the oncogenic BRAFV600E mutation in a high proportion (63%) of ameloblastoma samples.
BRAFV600E was the most common mutation, found in 62% of ameloblastomas and in ameloblastic fibromas/fibrodentinomas but not in other odontogenic tumors.
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.