Novel Targets for the Treatment of Ameloblastoma

Heikinheimo, Kristiina; Kurppa, Kari J.; Elenius, Klaus

doi:10.1177/0022034514560373

Cited by 59 publications

(72 citation statements)

References 15 publications

(44 reference statements)

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“…Additionally, several investigators identified a high incidence of mutually exclusive mutations in mitogen-activated protein kinase (MAPK) pathway genes (FGFR, BRAF V600E, and RAS family) and sonic hedgehog (SHH) signaling pathway gene SMO in ameloblastomas, providing potential avenues for targeted therapies with RTK, MEK, BRAF, and SMO inhibitors [22].…”

Section: Discussionmentioning

confidence: 99%

Ameloblastoma: 25 Year Experience at a Single Institution

Milman

Ying

Pan

et al. 2016

Head and Neck Pathol

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Ameloblastoma is a rare, locally aggressive odontogenic neoplasm, accounting for fewer than 1 % of head and neck tumors. Recent literature suggests that the initial surgical approach and histologic growth patterns are the most important prognostic determinants in ameloblastoma. The aim of this study was to compare the clinical presentation, management, and outcomes of patients with ameloblastoma with data reported in the literature; the study spanned 2 decades at a single institution. The institution's database was searched for all patients with pathologically confirmed ameloblastoma, diagnosed between 1990 and 2015. The data collected included sex, age, clinical and imaging findings, management, histologic pattern, clearance of surgical margins, length of follow-up, time to recurrence, and disease-related mortality. The potential risk factors of recurrence were evaluated using log-rank test, proportional hazard model, and Fisher exact test. Review of the database yielded 54 patients with pathologically confirmed ameloblastoma and follow-up. Recurrence was noted in 13 (24 %) patients. Surgical approach was associated with the risk of recurrence (6.1 % following radical resection vs. 52 % following limited surgery, p = 0.002). There were trends toward higher recurrence rate in the group with pathologically documented positive margins (p = 0.054) and in follicular ameloblastoma (p = 0.35). Transformation into ameloblastic carcinoma was identified in two patients. There was no disease-related mortality. Our study confirms the recent data regarding the importance of radical surgical resection in management of ameloblastoma. Surgical approach appears to be the strongest predictor of tumor clearance.

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Section: Discussionmentioning

confidence: 99%

Ameloblastoma: 25 Year Experience at a Single Institution

Milman

Ying

Pan

et al. 2016

Head and Neck Pathol

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“…Dentre os diversos marcadores imunohistoquímicos estudados em associação com os ameloblastomas, as moléculas envolvidas com vias de sinalização celular tem sido demonstradas como principais ativadoras da proliferação celular desorganizada nesses tumores (Kurppa et al, 2014;Brown et al, 2014;Heikinheimo et al, 2015). Trabalhos recentes demonstraram uma alta frequência da proteína mutada BRAF associadas aos ameloblastomas mandibulares (Kurppa et al, 2014;Brown et al, 2014;Heikinheimo et al, 2015).…”

Section: Lista De Figurasunclassified

“…Trabalhos recentes demonstraram uma alta frequência da proteína mutada BRAF associadas aos ameloblastomas mandibulares (Kurppa et al, 2014;Brown et al, 2014;Heikinheimo et al, 2015). Essa mutação é denominada de BRAF V600E e ocorre devido a substituição do aminoácido valina para acido glutâmico no número 600 (Kurppa et al, 2014 Portanto, a detecção da mutação BRAF V600E abriu novas perspectivas na compreensão da etiopatogenia dos ameloblastomas bem como nas modalidades de tratamento com terapias alvo e abordagens menos agressivas.…”

Section: Lista De Figurasunclassified

“…Devido a esses fatores, estudos de marcadores moleculares associados aos ameloblastomas tem sido realizados com o intuito de desenvolver terapias sistêmicas visando a busca de tratamentos mais conservadores, sem a necessidade de cirurgias extensas e/ou repetitivas (Brown et al, 2014;Kurppa et al, 2014;Sweeney et al, 2014;Heikinheimo et al, 2015).…”

Section: Revisão De Literaturaunclassified

“…Estudos recentes demonstraram a ativação da via MAPK em ameloblastomas e tumores com morfologia ameloblástica (Kurppa et al, 2014;Heikinheimo et al, 2015 Gaertner, Curitiba, PR.…”

Section: Revisão De Literaturaunclassified

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Análise imunohistoquímica da mutação BRAF V600E em ameloblastomas mandibulares

Canto¹

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Canto AM. Imunonhistochemical analysis of BRAF V600E mutation in ameloblastomas [Dissertation]. São Paulo: Universidade de São Paulo, Faculdade de Odontologia; 2017. Versão Original.Ameloblastoma is an aggressive odontogenic tumour, being locally invasive and highly recurrent. Studies have demonstrated that it is the most common benign odontogenic neoplasia, sometimes exhibiting behaviour of malignant lesions.Detection of BRAF V600E mutation has been shown to be one of the main proliferation pathways of ameloblastomas. Therefore, the identification of these markers can be useful to elaborate more efficient treatment strategies for this pathology as well as to improve the patient's quality of life. This study investigated the BRAF V600E mutation in mandible ameloblastomas by using the were male (52.38%) and 40 female (47.62%). The median age was 25.5 years old, with 42 cases having age below the median (50%) and 42 above it (50%). With regard to the presence or absence of BRAF V600E mutation, 66 cases were found to be positive for the marker (78.57%) and 18 were negative (21.43%). The correlation between BRAF expression and variables showed statistical significances for mandibular location (P = 0.0353) and tumour size (P = 0.008), whereas no statistical significance was observed for gender (P = 0.969), age (P = 1.0), radiographic aspect (P = 0.977), histological pattern (P = 0.910), histological subtype (P = 0.5141) and tumour status (P = 0.336). The authors concluded that BRAF V600E mutation is common in mandibular ameloblastomas, with tumours larger than four cm being more frequent in the posterior region of the mandible. In addition, this pathology occurs regardless of histological type of the tumour, age, gender, radiographic aspect and tumour status.

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BRAF V600E and previously unidentified KRAS G12C mutations in odontogenic tumors may affect MAPK activation differently depending on tumor type

Kim

Cho

et al. 2022

Genes Chromosomes & Cancer

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Although several types of odontogenic tumors share the same mutations in MAPK pathway genes, their effects on MAPK activation remain unclarified. This study aimed to evaluate the associations between these mutations and ERK phosphorylation in ameloblastoma and mixed odontogenic tumors (MOTs) and to analyze the expression pattern of phosphorylated ERK (p‐ERK) for determining the involvement of MAPK activation in the development and progression of odontogenic tumors. Forty‐three odontogenic tumors consisting of 18 ameloblastomas and 25 MOTs were analyzed for BRAF, KRAS, and NRAS mutations by Sanger sequencing. The expressions of BRAFV600E protein and p‐ERK were detected by immunohistochemistry. The associations between mutation status and p‐ERK expression were statistically analyzed. The effect of BRAFV600E inhibition on MAPK activation was investigated in ameloblastoma cells. In benign MOTs, BRAFV600E mutations were neither expressed at the protein level nor associated with p‐ERK expression. In contrast, BRAFV600E‐mutant ameloblastic fibrosarcoma showed co‐expression of BRAF V600E protein and p‐ERK, especially in the sarcomatous component. In ameloblastoma, p‐ERK was predominantly expressed in the tumor periphery showing a significant correlation with BRAFV600E mutations, and in vitro BRAFV600E inhibition decreased ERK phosphorylation. KRASG12C mutations, previously unidentified in odontogenic tumors, were detected in one case each of benign MOT and ameloblastoma; only the latter was high‐p‐ERK. In conclusion, unlike in benign MOTs, BRAFV600E and KRASG12C mutations lead to MAPK activation in ameloblastoma, suggesting their role as therapeutic targets. p‐ERK intratumoral heterogeneity indicates that MAPK pathway activation may be associated with sarcomatous proliferation of ameloblastic fibrosarcoma and infiltrative behavior of ameloblastoma.

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Novel Targets for the Treatment of Ameloblastoma

Cited by 59 publications

References 15 publications

Ameloblastoma: 25 Year Experience at a Single Institution

Ameloblastoma: 25 Year Experience at a Single Institution

Análise imunohistoquímica da mutação BRAF V600E em ameloblastomas mandibulares

BRAF V600E and previously unidentified KRAS G12C mutations in odontogenic tumors may affect MAPK activation differently depending on tumor type

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