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.
Highlights
Odontogenic tumors are uncommon lesions that originate from cells and tissues involved in odontogenesis and from their remnants
We considered the total number of assessed samples (n = 62), to calculate the frequency of KRAS, NRAS, HRas proto-oncogene GTPase (HRAS), and epidermal growth factor receptor (EGFR) mutations. hConsidering only the mandibular location, The study of Heikinheimo et al [58] described B-Raf proto-oncogene serine/threonine kinase (BRAF) p.V600E in 29/31 (93.5%) of unicystic ameloblastomas. *Mutually exclusive with BRAF p.V600E, except for one case harboring FGFR2 p.C382R and BRAF p.V600E. **This study reported BRAF p.V600E mutation in all five ameloblastic carcinoma samples evaluated and this frequency was much higher than reported by previous studies, and we did not add the results to the other ones when calculating mutation frequency. #Different detection methods were used in the studies to assess mutations, including allele-specific qPCR, next-generation sequencing, direct sequencing as well as immunohistochemistry
Their pathogenesis has not been entirely elucidated, the detection of pathogenic mutations in MAPK/ERK pathway genes in some odontogenic tumors strongly suggested that this pathway constitutive activation contributed to tumorigenesis
Summary
Odontogenic tumors are uncommon lesions that originate from cells and tissues involved in odontogenesis and from their remnants. These tumors comprise a heterogeneous group of lesions ranging from hamartomatous ones to benign and malignant neoplasms [1]. Odontogenic tumors are classified into epithelial, mesenchymal, and mixed epithelial and mesenchymal tumors based on the odontogenic tissue they mimic [1]. The pathogenesis of odontogenic tumors is associated with alterations in components of signaling pathways. Studies in the last decade have described pathogenic mutations in mitogen-activated protein kinases/extracellular signal-regulated kinases (MAPK/ERK) pathway cascade components in benign and malignant odontogenic tumors [3]
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