Genes and Genetic Pathways Regarding the Etiology and Pathogenesis of Ameloblastoma

<b>Background/Objectives:</b> Ameloblastoma is a benign odontogenic neoplasm characterized by locally aggressive behavior and frequent recurrences despite surgical treatment. It originates from odontogenic epithelium, including the cell rests of the dental lamina, remnants of the enamel organ, epithelial cell rests of Malassez, or the basal cell layer of the oral mucosa. Investigation of the etiopathogenesis of ameloblastoma has gained critical relevance due to the need for extensive surgical procedures, high recurrence rates, and its malignant potential. Accordingly, the aim of the present narrative review is to summarize current evidence regarding key aspects of ameloblastoma etiopathogenesis, with emphasis on signaling pathways, mutations, epigenetics, and epithelial-stromal interactions. <b>Methods:</b> An extensive literature search was conducted using the PubMed, Scopus, and Google Scholar databases, employing the keywords: "etiology", "pathogenesis", "molecular", "biomarkers", "cellular", "epigenetic", "mutation", "pathway", and "ameloblastoma". In vitro studies, clinical studies, case reports, and narrative and systematic reviews published in English were included, without restriction on publication year. <b>Results:</b> Current evidence indicates that ameloblastoma pathogenesis is driven by dysregulation of multiple signaling pathways, particularly the MAPK and Sonic Hedgehog pathways, through recurrent activating <i>BRAF</i> and <i>SMO</i> mutations. In addition, alterations affecting the WNT/β-Catenin and PI3K/AKT signaling cascades, epigenetic modifications, and epithelial-stromal interactions, contribute to tumor behavior. <b>Conclusions:</b> Despite significant advances, genotype-phenotype correlations, mutation frequencies and coexistence, clonality, and other associations remain incompletely understood. Larger tumor cohorts and robust meta-analyses are required to clarify these associations and to leverage the development of personalized therapeutic strategies.