**2. Etiopathogenesis**

The exact etiological factors associated with ameloblastoma are not yet completely understood. Up to 2014, little was known about exact molecular pathogenesis and a variety of etiological factors existed, including trauma, inflammation, dental caries and nutritional deficiencies [3, 7]. Considering ectodermal origin of ameloblastoma and its development from cells of the dental lamina, it is anticipated that enamel organ, cell rests of Malessez, cell rests of Serres and remnants of odontogenic epithelium are linked to etiopathogenesis of ameloblastoma [8].

As the genetic understanding increased, valuable findings have been brought to light regarding molecular pathogenesis of ameloblastoma. In 2014, it was confirmed that recurrent somatic and activating mutations in the mitogen-activated protein kinase (MAPK) plays a prominent role in the pathogenesis of the disease [6, 9, 10]. Additionally, there is evidence that mutations in non-MAPK signaling pathways, especially sonic hedgehog (SHH) pathway are also associated with ameloblastoma [11].

Mutations related to MAPK pathway include BRAF, fibroblast growth factor receptor 2 (FGFR2) and RAS genes [6, 9, 10]. BRAF is a serine/threonine protein kinase which activates the MAPK/ERK signaling pathway with consequential increase in cell proliferation and neoplastic transformation [6]. BRAF V600E mutations were firstly found in ameloblastoma clinical samples by Kurppa et al. [6] using real-time PCR enhanced by Sanger sequencing. These authors observed a high frequency of BRAF V600E mutations (63%). Subsequently, more recent studies described occurrence of the mutations ranging from 43% to 82% [7, 12, 13]. RAS is a protein that normally activates BRAF, therefore acts upstream of BRAF. In addition, the activation of RAS is normally triggered by the activation of FGFR2 which is a membrane-bound activator of MAPK signaling [14]. FGFR2 and RAS mutations were identified in up to 20% ameloblastoma cases [7]. Together, all the mentioned mutations are present in vast majority of ameloblastomas, suggesting that activation of the MAPK signaling pathway represents a critical event in the pathogenesis of ameloblastoma [2].

Several non-MAPK mutations have also been associated with ameloblastoma. The most important is nonclassical G protein-coupled receptor, the smoothened (SMO) gene. It is a signaling receptor that mediates SHH signaling pathway. Frequency rates of SMO mutations are lower than those in MAPK pathways, but these mutations have a greater tendency to appear in the maxillary ameloblastomas. Furthermore, SHH mutations including SMO appear to be associated with higher recurrence of the disease [7, 10].

*Perspective Chapter: Ameloblastoma – Present and Future Concepts of Managing DOI: http://dx.doi.org/10.5772/intechopen.107403*
