The Molecular Pathology of Odontogenic Tumors: Expanding the Spectrum of MAPK Pathway Driven Tumors

Abstract

Odontogenic tumors comprise a heterogeneous group of lesions that arise from the odontogenic apparatus and their remnants. Although the etiopathogenesis of most odontogenic tumors remains unclear, there have been some advances, recently, in the understanding of the genetic basis of specific odontogenic tumors. The mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) pathway is intimately involved in the regulation of important cellular functions, and it is commonly deregulated in several human neoplasms. Molecular analysis performed by different techniques, including direct sequencing, next-generation sequencing, and allele-specific qPCR, have uncovered mutations in genes related to the oncogenic MAPK/ERK signaling pathway in odontogenic tumors. Genetic mutations in this pathway genes have been reported in epithelial and mixed odontogenic tumors, in addition to odontogenic carcinomas and sarcomas. Notably, B-Raf proto-oncogene serine/threonine kinase (BRAF) and KRAS proto-oncogene GTPase (KRAS) pathogenic mutations have been reported in a high proportion of ameloblastomas and adenomatoid odontogenic tumors, respectively. In line with the reports about other neoplasms that harbor a malignant counterpart, the frequency of BRAF p.V600E mutation is higher in ameloblastoma (64% in conventional, 81% in unicystic, and 63% in peripheral) than in ameloblastic carcinoma (35%). The objective of this study was to review MAPK/ERK genetic mutations in benign and malignant odontogenic tumors. Additionally, such genetic alterations were discussed in the context of tumorigenesis, clinical behavior, classification, and future perspectives regarding therapeutic approaches.

Keywords: BRAF; KRAS; MAPK; ameloblastic; ameloblastoma; benign tumors; genetic mutations; odontogenic.

Figure 1

Canonical mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) signaling pathway under normal circumstances and in the presence of activating mutations. (A) Canonical RAS-RAF-MEK-ERK cascade and its normal activation by external signals (e.g., FGF and EGF growth factors) binding to receptor tyrosine kinases [e.g., fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (EGFR)]. This interaction triggers signaling through RAS-GTP, RAF, MEK, and ERK culminating with the action of phosphorylated ERK in its substrates and the regulation of cellular biological functions. In the absence of external stimulus, active RAS-GTP switches to its inactive form RAS-GDP by hydrolysis due to GAPs action. (B) In the presence of BRAF p.V600E mutation, BRAF constitutively activates MAPK/ERK signaling even in the absence of growth factors and dimerization with RAS, sustaining MAPK/ERK signaling. (C) Activating mutations in RAS genes (KRAS, NRAS, and HRAS) lead to unbalance between inactive and active RAS forms toward the active state (RAS-GTP) either by reducing GTP hydrolysis or by increasing the rate of GTP loading. This mechanism constitutively activates MAPK/ERK signaling even without external stimulus, sustaining its signals.

Figure 2

MAPK/ERK signaling pathway mutations in odontogenic tumors. BRAF p.V600E is the most common mutation in ameloblastomas, followed by KRAS (mostly p.G12R), NRAS, HRAS, and FGFR2 mutations reported in a few BRAF wild-type cases. Additionally, an EGFR mutation has also been reported in one ameloblastoma case. These less commonly reported mutations in ameloblastomas are indicated with an asterisk (*). Ameloblastic fibromas, ameloblastic fibrodentinomas, ameloblastic fibro-odontomas, ameloblastic fibrosarcoma, ameloblastic carcinomas, and clear cell odontogenic carcinoma (a single case) also carry BRAF p.V600E mutation. An NRAS mutation has also been reported in one case of ameloblastic fibrosarcoma in a mutually exclusive manner with BRAF p.V600E. Adenomatoid odontogenic tumors are characterized by frequent KRAS codon 12 (either p.G12V or p.G12R, and in a single case p.G12D) driver mutations, which occur in approximately 70% of cases. Detailed information on the studies reporting these mutations is shown in Table 1.