Ameloblastoma: A Review of Recent Molecular Pathogenetic Discoveries

Abstract

Ameloblastoma is an odontogenic neoplasm whose molecular pathogenesis has only recently been elucidated. The discovery of recurrent activating mutations in FGFR2, BRAF, and RAS in a large majority of ameloblastomas has implicated dysregulation of MAPK pathway signaling as a critical step in the pathogenesis of this tumor. Some degree of controversy exists regarding the role of mutations affecting the sonic hedgehog (SHH) pathway, specifically Smoothened (SMO), which have been postulated to serve as either an alternative pathogenetic mechanism or secondary mutations. Here, we review recent advances in our understanding of the molecular pathogenesis of ameloblastoma as well as the diagnostic, prognostic, and therapeutic implications of these discoveries.

Molecular Signaling in Benign Odontogenic Neoplasia Pathogenesis

“…This pathway can be activated by mutations in many of the pathway components, including receptors fibroblast growth factor receptor 2 ( FGFR2 ), downstream serine-threonine kinases ( BRAF ), and the Ras genes themselves ( HRAS, KRAS, NRAS ) [36]. These mutations can lead to constitutive activation of the mitogen-activated protein kinase (MAPK), resulting in the activation of downstream kinases such as MEK1 and ERK and the transcription of targets leading to proliferation and survival of cancer cells.…”

“…RAS and FGFR2 mutations were also identified in additional ameloblastoma samples. Brown and Betz (2015) summarized these studies, and indicated that 78–88% of ameloblastomas have an activating mutation in the Ras pathway, but rarely have mutations in more than one pathway component [36]. More recent studies have examined subtypes of ameloblastoma and other types of odontogenic tumors.…”

BRAF‐V600E expression correlates with ameloblastoma aggressiveness

“…As the molecular basis of ameloblastoma is not well understood, surgery remains the gold standard therapy. However, recent studies have reported novel molecular findings that shed new insights into understanding the mechanisms, pathogenesis and management of ameloblastoma …”

Ameloblastoma—Clinical, radiological, and therapeutic findings

“…This mutation is also found in other malignant tumors such as melanoma, papillary thyroid cancer, and colorectal cancer (Brown & Betz, ). The mutation of BRAF‐V600E results in overexpression of the BRAF protein resulting in the activation of extracellular signal‐regulated kinase signaling further down the pathway resulting in activation of transcriptional factors leading to malignant transformation and growth (Brown & Betz, ). Patients displaying a BRAF‐V600E mutation may be eligible for target therapy using a combination of dabrafenib ((BRAF inhibitor) and trametinib (MEK inhibitor).…”

“…Patients displaying a BRAF‐V600E mutation may be eligible for target therapy using a combination of dabrafenib ((BRAF inhibitor) and trametinib (MEK inhibitor). Case reports have shown excellent responses to this treatment even after formation of metastasis in malignant ameloblastoma (Brown & Betz, ). Although not yet confirmed in larger studies, this may be a treatment option for the future that might spare radical surgery and thus reduce the treatment‐associated morbidity in patients with ameloblastomas.…”