Genomic and transcriptomic analysis of ameloblastoma reveals distinct molecularly aggressive phenotypes

Ameloblastoma (AM) is a benign but locally infiltrative epithelial odontogenic neoplasm of the jawbones that may reach grotesque proportions and be highly recurrent if inadequately removed. The BRAFV600E mutation has been demonstrated as a key molecular event in its development; nevertheless, there are many queries about its etiopathogenesis, which are yet to be answered. In this study, we aimed to integrate the results from whole-exome sequencing (WES) and RNA sequencing in AM samples to identify novel candidate genes that may be relevant to its pathogenesis. Thirteen-matched tumors were subjected to WES and RNA-seq, respectively, to detect gene mutations and gene expression profiles, along with the presence of gene fusions. Mutations were validated using Sanger sequencing, whereas transcriptome results were validated using qPCR. The results from both molecular techniques were merged in order to identify novel candidate genes that were biologically validated with immunohistochemistry. BRAFV600E mutation was present in 62% of the analyzed cases, and each AM presented at least 2 or 3 mutations affecting cancer-driver genes. RNA-seq showed different molecular subgroups associated with an aggressive and cancer-related phenotype (epithelial-mesenchymal transition and KRAS gene sets). No gene fusions were detected among the cases. CDH11 and TGM2, novel genes associated with epithelial-mesenchymal transition in AM, were selected and validated in tissues. Both WES and RNA-seq results showed gene alterations related to proliferation, cell differentiation, and metabolic processes. These results show that AM shares many of the hallmarks of cancer secondary to the presence of oncogenic mutations or activation of oncogenic signaling pathways.