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Marín-Márquez C, Adisa AO, Niklander SE, Kirby J, Hunter KD. Genomic and Transcriptomic Analysis of Ameloblastoma Reveals Distinct Molecularly Aggressive Phenotypes. Mod Pathol 2025; 38:100682. [PMID: 39675431 DOI: 10.1016/j.modpat.2024.100682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2024] [Revised: 12/02/2024] [Accepted: 12/04/2024] [Indexed: 12/17/2024]
Abstract
Ameloblastoma (AM) is a benign but locally infiltrative epithelial odontogenic neoplasm of the jawbones that may reach grotesque proportions and be highly recurrent if inadequately removed. The BRAFV600E mutation has been demonstrated as a key molecular event in its development; nevertheless, there are many queries about its etiopathogenesis, which are yet to be answered. In this study, we aimed to integrate the results from whole-exome sequencing (WES) and RNA sequencing in AM samples to identify novel candidate genes that may be relevant to its pathogenesis. Thirteen-matched tumors were subjected to WES and RNA-seq, respectively, to detect gene mutations and gene expression profiles, along with the presence of gene fusions. Mutations were validated using Sanger sequencing, whereas transcriptome results were validated using qPCR. The results from both molecular techniques were merged in order to identify novel candidate genes that were biologically validated with immunohistochemistry. BRAFV600E mutation was present in 62% of the analyzed cases, and each AM presented at least 2 or 3 mutations affecting cancer-driver genes. RNA-seq showed different molecular subgroups associated with an aggressive and cancer-related phenotype (epithelial-mesenchymal transition and KRAS gene sets). No gene fusions were detected among the cases. CDH11 and TGM2, novel genes associated with epithelial-mesenchymal transition in AM, were selected and validated in tissues. Both WES and RNA-seq results showed gene alterations related to proliferation, cell differentiation, and metabolic processes. These results show that AM shares many of the hallmarks of cancer secondary to the presence of oncogenic mutations or activation of oncogenic signaling pathways.
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Affiliation(s)
- Constanza Marín-Márquez
- Unit of Oral and Maxillofacial Medicine, Pathology and Surgery, University of Sheffield, Sheffield, UK; Facultad de Odontología y Ciencias de la Rehabilitación, Universidad San Sebastián, Puerto Montt, Chile.
| | - Akinyele O Adisa
- Department of Oral Pathology, Faculty of Dentistry, University of Ibadan and University College Hospital Ibadan, Ibadan, Nigeria
| | - Sven E Niklander
- Unit of Oral Pathology and Oral Medicine, Faculty of Dentistry, Universidad Andres Bello, Viña del Mar, Chile
| | - Janine Kirby
- Sheffield Institute for Translational Neuroscience, Division of Neuroscience, School of Medicine and Population Health, University of Sheffield, Sheffield, UK
| | - Keith D Hunter
- Liverpool Head and Neck Centre, Molecular and Clinical Cancer Medicine, University of Liverpool, UK
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Aouam O, Janssen NG, de Leng WWJ, Breimer GE. Ameloblastic Fibro-Odontoma with an FGFR1 Mutation: A Case Report. Head Neck Pathol 2025; 19:19. [PMID: 39907837 PMCID: PMC11799477 DOI: 10.1007/s12105-025-01758-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2024] [Accepted: 01/25/2025] [Indexed: 02/06/2025]
Abstract
PURPOSE Ameloblastic fibro-odontoma (AFO) is a rare benign mixed odontogenic tumor that, after being classified for years as a distinct entity, was redefined as a "developing odontoma" in the 2017 World Health Organization classification. This article presents a unique case of an AFO with an FGFR1 mutation. METHODS We present a case of an 8-year-old child with a slowly progressive swelling in the lower left mandible. Next-generation sequencing (TSO500 panel) was performed. RESULTS Panoramic radiography revealed an odontogenic tumor; therefore, a transoral enucleation was performed. Pathological microscopic examination confirmed the diagnosis of AFO, and next-generation sequencing detected an FGFR1 mutation. CONCLUSION The presence of an FGFR1 mutation in an AFO may suggest a closer biological relationship between ameloblastic fibroma and AFO, potentially distinguishing it from odontomas. Further research, including genetic studies, is needed to enhance our understanding and refine the classification of these tumors.
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Affiliation(s)
- Oumaima Aouam
- Department of Pathology, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands
| | - Nard G Janssen
- Department of Oral and Maxillofacial Pediatric Surgery, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Wendy W J de Leng
- Department of Pathology, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands
| | - Gerben E Breimer
- Department of Pathology, University Medical Center Utrecht, Utrecht, 3584 CX, The Netherlands.
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Mishra S, Panda S, Mohanty N, Mishra S, Gopinath D, Panda S, Anil S. Differential Expression of Immunohistochemical Markers in Ameloblastoma & Ameloblastic Carcinoma: A Systematic Review and Meta-analysis of observational studies. F1000Res 2024; 13:557. [PMID: 39082057 PMCID: PMC11287113 DOI: 10.12688/f1000research.149861.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/20/2024] [Indexed: 08/02/2024] Open
Abstract
BACKGROUND Differentiating between ameloblastoma (AB) and ameloblastic carcinoma (AC) is difficult, especially when AB has atypical cytological characteristics or an uncommon clinical history. This systematic review and meta-analysis aimed to elucidate the differential expression of immunohistochemical markers between AB and AC. METHODS We conducted a thorough search of PUBMED and SCOPUS according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify cross-sectional studies that compared the expression of immunohistochemical markers in AB and AC. We used a random-effects model to analyze the risk ratios and their corresponding 95% confidence intervals (CIs). The quality of the included studies was assessed using the Newcastle-Ottawa scale. The Egger's test was used to assess publication bias. RESULTS In total, 301 articles were identified. After excluding irrelevant titles and abstracts, 86 articles were selected for full-text review. We categorized the 41 markers into proliferative and non-proliferative markers. Among non-proliferative markers, nuclear markers were differentially expressed in AB and AC. SOX2 was the only marker that significantly differentiated AB and AC, with an RR of -0.19 (CI 0.10-0.36, I2=0). CONCLUSION The current evidence suggests the significance of SOX2 in differentiating between AB and AC, warranting prospective confirmation in well-defined extensive studies. We highlight the paucity of high-quality replicated studies of other markers in this field. Collaborative efforts with standardized techniques are necessary to generate clinically useful immunohistochemical markers.
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Affiliation(s)
- Saleena Mishra
- Department of Oral Pathology and Microbiology, Institute of Dental Sciences, Siksha O Anusandhan University, Bhubaneswar, Odisha, India
| | - Swagatika Panda
- Department of Oral Pathology and Microbiology, Institute of Dental Sciences, Siksha O Anusandhan University, Bhubaneswar, Odisha, India
| | - Neeta Mohanty
- Department of Oral Pathology and Microbiology, Institute of Dental Sciences, Siksha O Anusandhan University, Bhubaneswar, Odisha, India
| | - Swati Mishra
- General Dental Practitioner, Odisha, 757001, India
| | - Divya Gopinath
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, Ajman, United Arab Emirates
- Basic Medical and Dental Sciences Dept, Ajman University, Ajman, Ajman, United Arab Emirates
| | - Saurav Panda
- Department of Periodontics and Implantology, Institute of Dental Sciences, Siksha O Anusandhan University, Bhubaneswar, Odisha, India
| | - Sukumaran Anil
- Department of Dentistry, Oral Health Institute, Hamad Medical Corporation, Doha, Doha, Qatar
- Qatar University, Doha, Doha, Qatar
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Marín-Márquez C, Kirby J, Hunter KD. Molecular pathogenesis of ameloblastoma. J Oral Pathol Med 2024; 53:277-293. [PMID: 38664938 DOI: 10.1111/jop.13538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 03/08/2024] [Accepted: 04/08/2024] [Indexed: 05/16/2024]
Abstract
Ameloblastoma (AM) is a benign, although aggressive, epithelial odontogenic tumour originating from tooth-forming tissues or remnants. Its aetiopathogenesis remains unclear; however, molecular analysis techniques have allowed researchers to progress in understanding its genetic basis. The high frequency of BRAF p.V600E as a main driver mutation in AM is well established; nevertheless, it is insufficient to explain its tumourigenesis. In this review, we aimed to integrate the current knowledge about the biology of AM and to describe the main genetic alterations reported, focusing on the findings of large-scale sequencing and gene expression profiling techniques. Current evidence shows that besides BRAF mutation and activation of the MAPK pathway, alterations in Hedgehog and Wnt/β-catenin pathway-related genes are also involved in AM pathogenesis. Recently, a tumour suppressor gene, KMT2D, has been reported as mutated by different research groups. The biological impact of these mutations in the pathogenesis of AM has yet to be elucidated. Further studies are needed to clarify the impact of these findings in the identification of novel biomarkers that could be useful for diagnosing, classifying, and molecular targeting this neoplasm.
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Affiliation(s)
- Constanza Marín-Márquez
- Unit of Oral and Maxillofacial Medicine, Pathology and Surgery, University of Sheffield, Sheffield, UK
- Facultad de Odontología y Ciencias de la Rehabilitación, Universidad San Sebastián, Puerto Montt, Chile
| | - Janine Kirby
- Department of Neuroscience, Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, UK
| | - Keith D Hunter
- Liverpool Head and Neck Centre, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
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Tosios KI, Kalogirou EM, Koutlas IG. Association of MDM2 Overexpression in Ameloblastomas with MDM2 Amplification and BRAF V600E Expression. Int J Mol Sci 2024; 25:2238. [PMID: 38396916 PMCID: PMC10889355 DOI: 10.3390/ijms25042238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 02/01/2024] [Accepted: 02/09/2024] [Indexed: 02/25/2024] Open
Abstract
Ameloblastoma is a rare tumor but represents the most common odontogenic neoplasm. It is localized in the jaws and, although it is a benign, slow-growing tumor, it has an aggressive local behavior and high recurrence rate. Therefore, alternative treatment options or complementary to surgery have been evaluated, with the most promising one among them being a targeted therapy with the v-Raf murine sarcoma viral oncogene homologue B (BRAF), as in ameloblastoma the activating mutation V600E in BRAF is common. Studies in other tumors have shown that the synchronous inhibition of BRAF and human murine double minute 2 homologue (MDM2 or HDM2) protein is more effective than BRAF monotherapy, particularly in the presence of wild type p53 (WTp53). To investigate the MDM2 protein expression and gene amplification in ameloblastoma, in association with BRAFV600E and p53 expression. Forty-four cases of ameloblastoma fixed in 10% buffered formalin and embedded in paraffin were examined for MDM2 overexpression and BRAFV600E and p53 expression by immunohistochemistry, and for MDM2 ploidy with fluorescence in situ hybridization. Sixteen of forty-four (36.36%) cases of ameloblastoma showed MDM2 overexpression. Seven of sixteen MDM2-positive ameloblastomas (43.75%) were BRAFV600E positive and fifteen of sixteen MDM2-positive ameloblastomas (93.75%) were p53 negative. All MDM2 overexpressing tumors did not show copy number alterations for MDM2. Overexpression of MDM2 in ameloblastomas is not associated with MDM2 amplification, but most probably with MAPK activation and WTp53 expression. Further verification of those findings could form the basis for the use of MDM2 expression as a marker of MAPK activation in ameloblastomas and the trial of dual BRAF/MDM2 inhibition in the management of MDM2-overexpressing/BRAFV600E-positive/WTp53 ameloblastomas.
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Affiliation(s)
- Konstantinos I. Tosios
- Department of Oral Pathology & Medicine and Hospital Dentistry, School of Dentistry, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Eleni-Marina Kalogirou
- Faculty of Health and Rehabilitation Sciences, Metropolitan College, 15125 Athens, Greece;
| | - Ioannis G. Koutlas
- Division of Oral Pathology, School of Dentistry, University of Minnesota, Minneapolis, MN 55455, USA;
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Oh KY. Treatment options for advanced ameloblastoma in the era of precision medicine: A brief review. Oral Oncol 2023; 146:106585. [PMID: 37816291 DOI: 10.1016/j.oraloncology.2023.106585] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Accepted: 10/05/2023] [Indexed: 10/12/2023]
Abstract
Although complete excision is the standard of care for ameloblastoma, a subset of recurrent and/or metastasizing ameloblastomas are difficult to treat surgically. Over the past decade, several recurrent mutations in the mitogen-activated protein kinase pathway genes have been identified in ameloblastoma, based on which the efficacy of targeted therapy has been investigated. However, most of the literature has focused on BRAF V600E mutations, the most common oncogenic mutations in ameloblastoma. Hence, this study aims to review the current knowledge of targetable genetic alterations in ameloblastoma from a broader perspective. In addition, the therapeutic potential of immunotherapy for ameloblastoma will be briefly discussed in the context of tumoral PD-L1 expression and the tumor immune microenvironment.
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Affiliation(s)
- Kyu-Young Oh
- Department of Oral Pathology, College of Dentistry, Dankook University, Cheonan, Republic of Korea.
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Mamat @ Yusof MN, Ch’ng ES, Radhiah Abdul Rahman N. BRAF V600E Mutation in Ameloblastoma: A Systematic Review and Meta-Analysis. Cancers (Basel) 2022; 14:5593. [PMID: 36428683 PMCID: PMC9688909 DOI: 10.3390/cancers14225593] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 10/25/2022] [Accepted: 11/09/2022] [Indexed: 11/16/2022] Open
Abstract
The discovery that ameloblastoma has a high mutation incidence of BRAF V600E may enable a better investigation of pathophysiology. However, there is inconsistent evidence regarding this mutation occurrence and its association with clinical information. This systematic review and meta-analysis aim to pool the overall mutation prevalence of BRAF V600E in reported ameloblastoma cases and to determine its association with patient demographic and clinicopathological features. Following the PRISMA guidelines, a comprehensive article search was conducted through four databases (Scopus, Google Scholar, PubMed, and Web of Science). Seventeen articles between 2014 and 2022 met the inclusion criteria with 833 ameloblastoma cases. For each included study, the significance of BRAF V600E on the outcome parameters was determined using odd ratios and 95% confidence intervals. Meta-analysis prevalence of BRAF V600E in ameloblastoma was 70.49%, and a significant meta-analysis association was reported for those younger than 54 years old and in the mandible. On the contrary, other factors, such as sex, histological variants, and recurrence, were insignificant. As a result of the significant outcome of BRAF V600E mutation in ameloblastoma pathogenesis, targeted therapy formulation can be developed with this handful of evidence.
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Affiliation(s)
- Mohd Nazzary Mamat @ Yusof
- Department of Clinical Medicine, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas 13200, Malaysia
- Department of Obstetrics and Gynaecology, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur 56000, Malaysia
| | - Ewe Seng Ch’ng
- Department of Clinical Medicine, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas 13200, Malaysia
| | - Nawal Radhiah Abdul Rahman
- Department of Dental Science, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas 13200, Malaysia
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8
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Chen IY, Giampoli EJ, Zhang D. Ameloblastic Carcinoma of the Maxilla: A Rare Case Report and Review of Literature from 1948 to 2021. Int J Surg Pathol 2022; 31:442-454. [PMID: 35668625 DOI: 10.1177/10668969221102542] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Ameloblastic carcinoma is a rare malignant neoplasm arising from the odontogenic epithelium. Ameloblastic carcinoma commonly occurs de novo affecting the posterior segments of the mandible. Presently, only less than 100 cases have been reported arising from the maxilla. We report a unique case of maxillary ameloblastic carcinoma in a 68-year-old male with a 5.6 cm positron emission tomography (PET) avid left maxillary sinus mass. The patient underwent a left maxillectomy which revealed hyperchromatic and pleomorphic tumor cells arranged in a nested and trabecular architecture. The tumor cells showed distinct peripheral palisading with reverse polarization. Areas of bone destruction, necrosis, lymphovascular and perineural invasions, as well as atypical mitoses, were identified. Immunohistochemically, the tumor cells were positive for keratin cocktail (AE1/AE3 and CAM 5.2), keratin 19, p40, and weakly positive for MDM2, while negative for calretinin. Molecular analysis revealed wild-type BRAF; however, alterations in CDKN2A/B, MTAP, RB1, SMARCA4, STK11, FGF12, SETD2, and TP53 were present. This histopathologic and molecular profile supported the diagnosis of ameloblastic carcinoma. There has been no evidence of disease recurrence or metastasis eleven months after the initial diagnosis.
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Affiliation(s)
- Irene Y Chen
- Department of Pathology and Laboratory Medicine, 6923University of Rochester Medical Center, Rochester, NY, USA
| | - Ellen J Giampoli
- Department of Pathology and Laboratory Medicine, 6923University of Rochester Medical Center, Rochester, NY, USA
| | - Dongwei Zhang
- Department of Pathology and Laboratory Medicine, 1772Indiana University, Indianapolis, IN, USA
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9
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Guimarães LM, Coura BP, Gomez RS, Gomes CC. The Molecular Pathology of Odontogenic Tumors: Expanding the Spectrum of MAPK Pathway Driven Tumors. FRONTIERS IN ORAL HEALTH 2022; 2:740788. [PMID: 35048058 PMCID: PMC8757814 DOI: 10.3389/froh.2021.740788] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 08/13/2021] [Indexed: 12/13/2022] Open
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.
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Affiliation(s)
- Letícia Martins Guimarães
- Department of Pathology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Bruna Pizziolo Coura
- Department of Pathology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Ricardo Santiago Gomez
- Department of Oral Surgery and Pathology, Faculty of Dentistry, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Carolina Cavalieri Gomes
- Department of Pathology, Biological Sciences Institute, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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Marín C, Niklander SE, Martínez-Flores R. Genetic Profile of Adenomatoid Odontogenic Tumor and Ameloblastoma. A Systematic Review. FRONTIERS IN ORAL HEALTH 2022; 2:767474. [PMID: 35048068 PMCID: PMC8757772 DOI: 10.3389/froh.2021.767474] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 10/18/2021] [Indexed: 11/13/2022] Open
Abstract
Purpose: To perform a comprehensive and systematic critical appraisal of the genetic alterations reported to be present in adenomatoid odontogenic tumor (AOT) compared to ameloblastoma (AM), to aid in the understanding in their development and different behavior. Methods: An electronic search was conducted in PubMed, Scopus, and Web of Science during March 2021. Eligibility criteria included publications on humans which included genetic analysis of AOT or AM. Results: A total of 43 articles reporting 59 AOTs and 680 AMs were included. Different genomic techniques were used, including whole-exome sequencing, direct sequencing, targeted next-generation sequencing panels and TaqMan allele-specific qPCR. Somatic mutations affecting KRAS were identified in 75.9% of all AOTs, mainly G12V; whereas a 71% of the AMs harbored BRAF mutations, mainly V600E. Conclusions: The available genetic data reports that AOTs and AM harbor somatic mutations in well-known oncogenes, being KRAS G12V/R and BRAFV600E mutations the most common, respectively. The relatively high frequency of ameloblastoma compared to other odontogenic tumors, such as AOT, has facilitated the performance of different sequencing techniques, allowing the discovery of different mutational signatures. On the contrary, the low frequency of AOTs is an important limitation for this. The number of studies that have a assessed the genetic landscape of AOT is still very limited, not providing enough evidence to draw a conclusion regarding the relationship between the genomic alterations and its clinical behavior. Thus, the presence of other mutational signatures with clinical impact, co-occurring with background KRAS mutations or in wild-type KRAS cases, cannot be ruled out. Since BRAF and RAS are in the same MAPK pathway, it is interesting that ameloblastomas, frequently associated with BRAFV600E mutation have aggressive clinical behavior, but in contrast, AOTs, frequently associated with RAS mutations have indolent behavior. Functional studies might be required to solve this question.
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Affiliation(s)
- Constanza Marín
- Unidad de Patología y Medicina Oral, Facultad de Odontología, Universidad Andres Bello, Viña del Mar, Chile.,Unit of Oral and Maxillofacial Medicine, Pathology and Surgery, University of Sheffield, Sheffield, United Kingdom
| | - Sven E Niklander
- Unidad de Patología y Medicina Oral, Facultad de Odontología, Universidad Andres Bello, Viña del Mar, Chile
| | - René Martínez-Flores
- Unidad de Patología y Medicina Oral, Facultad de Odontología, Universidad Andres Bello, Viña del Mar, Chile
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11
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Lapthanasupkul P, Laosuk T, Ruangvejvorachai P, Aittiwarapoj A, Kitkumthorn N. Frequency of BRAF V600E mutation in a group of Thai patients with ameloblastomas. Oral Surg Oral Med Oral Pathol Oral Radiol 2020; 132:e180-e185. [PMID: 32665205 DOI: 10.1016/j.oooo.2020.06.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 04/15/2020] [Accepted: 06/01/2020] [Indexed: 12/28/2022]
Abstract
OBJECTIVE BRAF V600E mutation has recently been reported in a high proportion of ameloblastomas. This study was conducted to investigate the frequency of this mutation in ameloblastoma and unicystic ameloblastoma. The correlation between clinicopathologic data and BRAF V600E mutation was also analyzed. STUDY DESIGN A total of 51 archival samples of ameloblastomas and 22 cases of unicystic ameloblastomas were examined for BRAF V600E mutation by using anti-BRAF V600E (clone VE1) immunohistochemistry. RESULTS Positivity for anti-BRAF V600E antibody was detected in 72.5% (37 of 51) of ameloblastomas, but the mutation showed no significant correlation with the clinicopathologic parameters. With regard to unicystic ameloblastoma, 95.5% (21) of the 22 cases exhibited positive immunostaining for BRAF V600E, whereas only 1 case showed the mural subtype of wild-type BRAF. CONCLUSIONS A high frequency of BRAF V600E mutation was detected in a group of Thai patients with ameloblastomas, suggesting the future use of BRAF-targeted therapy in patients with BRAF-mutated ameloblastoma. However, no significant association between BRAF V600E mutation and the clinicopathologic characteristics of ameloblastomas was found in our study.
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Affiliation(s)
- Puangwan Lapthanasupkul
- Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, Mahidol University, Bangkok, Thailand
| | - Tuntikorn Laosuk
- Department of Biochemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand
| | | | - Anchisa Aittiwarapoj
- Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, Mahidol University, Bangkok, Thailand
| | - Nakarin Kitkumthorn
- Department of Oral Biology, Faculty of Dentistry, Mahidol University, Bangkok, Thailand.
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12
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Jastania RA, Saeed M, Al-Khalidi H, AlQuthami K, Nageeti TH, Al-Allaf FA, Valerie K, Taher MM. Adamantinomatous Craniopharyngioma in an Adult: A Case Report with NGS Analysis. Int Med Case Rep J 2020; 13:123-137. [PMID: 32368160 PMCID: PMC7183340 DOI: 10.2147/imcrj.s243405] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2019] [Accepted: 03/25/2020] [Indexed: 12/19/2022] Open
Abstract
PURPOSE Several recent studies have documented CTNNB1 and BRAF mutations which are mutually exclusive for adamantinomatous craniopharyngioma (ACP) and papillary craniopharyngioma (PCP) tumors. This discovery is helpful in the development of novel targeted therapies in successful clinical trials with BRAF mutations in PCP cases. However, no such targeted therapy is available yet for ACP. Here, we report novel mutations, which are not previously reported, in a case of an adult ACP using NGS analysis. RESULTS Patient DNA was sequenced using Ion PI v3 chip on Ion Proton. A total of 16 variants were identified in this tumor by NGS analysis, out of which four were missense mutations, seven were synonymous mutations, and five were intronic variants. In CTNNB1 gene a known missense mutation in c.101G>T; in TP53 a known missense mutation in c.215C>G; and two known missense variants in PIK3CA, viz., in c.1173A>G; in exon 7, and in c.3128T>C; in exon 21, were found, respectively. Seven synonymous mutations were detected in this tumor, viz., in IDH1 (rs11554137), in FGFR3 (rs7688609), in PDGFRA (rs1873778), in APC (COSM3760869), in EGFR (rs1050171), in MET (rs35775721), and in RET (rs1800861), respectively. Three known, intronic variants were found in genes, such as PIK3CA, KDR, and JAK3, respectively. Also, a 3'-UTR and a splice site acceptor site variant in CSF1R and FLT3 genes were found in this tumor. We have shown allele coverage, allele ratio, and p-value, for all these mutations. The p-values and Phred quality score were significantly high for these variants. CONCLUSION As reported in previous studies, in ACP tumors we found a CTNNB1 mutation by NGS analysis. The PIK3CA variants we detected were not known previously in ACP tumors. Finding the PIK3CA mutations in the ACP tumors may help develop targeted therapy for a subset of craniopharyngiomas with PIK3CA activating mutations. Clinical trials are in progress with specific PIK3CA inhibitors in advanced stages of many cancers.
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Affiliation(s)
- Raid A Jastania
- Department of Pathology, Faculty of Medicine, Umm-Al-Qura University, Makkah, Saudi Arabia
| | - Muhammad Saeed
- Department of Radiology, Faculty of Medicine, Umm-Al-Qura University, Makkah, Saudi Arabia
- Department of Radiology, Al-Noor Specialty Hospital, Makkah, Saudi Arabia
| | | | - Khalid AlQuthami
- Division of Histopathology, Department of Laboratory Medicine and Blood Bank, Al-Noor Specialty Hospital, Makkah, Saudi Arabia
| | - Tahani H Nageeti
- Department of Radiation Oncology, King Abdullah Medical City, Makkah, Saudi Arabia
| | - Faisal A Al-Allaf
- Science and Technology Unit, Umm-Al-Qura University, Makkah, Saudi Arabia
- Department of Medical Genetics, Faculty of Medicine, Umm-Al-Qura University, Makkah, Saudi Arabia
| | - Kristoffer Valerie
- Department of Radiation Oncology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Mohiuddin M Taher
- Science and Technology Unit, Umm-Al-Qura University, Makkah, Saudi Arabia
- Department of Medical Genetics, Faculty of Medicine, Umm-Al-Qura University, Makkah, Saudi Arabia
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13
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Agaimy A, Skalova A, Franchi A, Alshagroud R, Gill AJ, Stoehr R, Baumhoer D, Bauer S. Ameloblastic fibrosarcoma: clinicopathological and molecular analysis of seven cases highlighting frequent BRAF and occasional NRAS mutations. Histopathology 2020; 76:814-821. [PMID: 31899815 DOI: 10.1111/his.14053] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 12/18/2019] [Accepted: 12/21/2019] [Indexed: 12/21/2022]
Abstract
AIMS Ameloblastic fibrosarcoma (AFS) is an aggressive odontogenic neoplasm featuring malignant mesenchymal stroma in addition to an ameloblastic epithelial component, and is hence considered to be the malignant counterpart of ameloblastic fibroma (AF). AFS is exceedingly rare, with <110 cases having been reported so far. Although BRAF mutations are recognised driver mutations in ameloblastoma, the molecular pathogenesis of AFS remains elusive. METHODS AND RESULTS We herein describe seven AFSs that were analysed, for the first time, for mutations in the BRAF-NRAS pathway. The patients were four females and three males aged 23-57 years (median, 26 years). Three tumours developed after one or multiple recurrences of AF (4-20 years after initial diagnosis), two showed transition from AF-like bland areas, and two developed de novo. All patients were treated with surgery; adjuvant chemotherapy was given to one patient. At the last follow-up, five patients were alive and well (19-344 months). The remainder were lost to follow-up. Histological examination showed variable sarcomatous overgrowth with varying degrees of atypia and increased mitotic activity. The epithelial component varied greatly according to the degree of sarcomatous overgrowth. Molecular testing revealed BRAF V600E mutations in five cases and NRAS p.Gln61Lys mutation in one case. One tumour was wild-type. CONCLUSION To our knowledge, this is the first study on BRAF/NRAS mutations in AFS. Given the activity of RAF and MEK inhibitors across different cancers harbouring V600E mutations, our data strongly suggest that all AFS cases should be genetically tested, and that targeted treatment approaches for this extremely rare sarcoma subtype should be clinically investigated.
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Affiliation(s)
- Abbas Agaimy
- Institute of Pathology, University Hospital, Erlangen, Germany
| | - Alena Skalova
- Department of Pathology, Charles University, Faculty of Medicine in Plzen, Plzen, Czech Republic
| | - Alessandro Franchi
- Department of Translational Research, School of Medicine, University of Pisa, Pisa, Italy
| | - Rana Alshagroud
- Department of Oral Medicine and Diagnostic Science, King Saud University, Riyadh, Saudi Arabia
| | - Anthony J Gill
- Sydney Medical School University of Sydney, St Leonards, NSW, Australia.,Cancer Diagnosis and Pathology Group, Kolling Institute, St Leonards, NSW, Australia.,NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, NSW, Australia
| | - Robert Stoehr
- Institute of Pathology, University Hospital, Erlangen, Germany
| | - Daniel Baumhoer
- Department of Pathology, University Hospital Basel, Basel, Switzerland
| | - Sebastian Bauer
- Sarcoma Centre, Western German Cancer Centre, University of Duisburg-Essen Medical School, Essen, Germany
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14
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Duarte-Andrade FF, Vitório JG, Pereira TDSF, Gomes CC, Gomez RS. A review of the molecular profile of benign and malignant odontogenic lesions. Oral Surg Oral Med Oral Pathol Oral Radiol 2020; 129:357-368. [PMID: 32035859 DOI: 10.1016/j.oooo.2019.12.017] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 12/27/2019] [Accepted: 12/29/2019] [Indexed: 12/16/2022]
Abstract
Odontogenic cysts and tumors are heterogeneous lesions, originating from elements or remnants of the odontogenic apparatus. Although the majority of these lesions are benign and never undergo malignant transformation, rare malignant tumors may arise de novo or from benign precursors. The molecular basis of these lesions is still poorly understood. This article summarizes and discusses studies using small, medium, and large-scale and/or "-omic" techniques to describe the molecular characteristics of benign and malignant odontogenic lesions and briefly debates strategies to increase the use of "-omic" and multi-omic approaches or integrative analyses in the research of these lesions. A comprehensive understanding of the molecular aspects of odontogenic lesions by using large-scale approaches will enable us to refine the classification of this heterogeneous group of disorders and provide more accurate biomarkers for precise diagnosis, prognosis, and development of molecular tools in the management of patients with these conditions.
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Affiliation(s)
- Filipe Fideles Duarte-Andrade
- Department of Oral Surgery and Pathology, School of Dentistry, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Jéssica Gardone Vitório
- Department of Oral Surgery and Pathology, School of Dentistry, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Thaís Dos Santos Fontes Pereira
- Department of Oral Surgery and Pathology, School of Dentistry, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Carolina Cavaliéri Gomes
- Department of Pathology, Biological Sciences Institute, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Ricardo Santiago Gomez
- Department of Oral Surgery and Pathology, School of Dentistry, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
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15
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González-González R, López-Verdín S, Lavalle-Carrasco J, Molina-Frechero N, Isiordia-Espinoza M, Carreón-Burciaga RG, Bologna-Molina R. Current concepts in ameloblastoma-targeted therapies in B-raf proto-oncogene serine/threonine kinase V600E mutation: Systematic review. World J Clin Oncol 2020; 11:31-42. [PMID: 31976308 PMCID: PMC6935689 DOI: 10.5306/wjco.v11.i1.31] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 10/23/2019] [Accepted: 11/06/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Ameloblastomas are common benign epithelial odontogenic neoplasms that present an aggressive and unpredictable behavior that may modify treatment strategies. Different signaling pathways that participate in the progression of these tumors have been identified. B-raf proto-oncogene serine/threonine kinase (BRAF) is a protein involved in the behavior of ameloblastomas, and it is related to many cell mechanisms. BRAF gene mutations have been identified in ameloblastomas, of which the BRAF V600E (valine substituted by glutamic acid at amino acid 600) mutation has been the most common and can be present concomitantly with other mutations that may be involved in its behavior. Targeted therapies have been used as an alternative in the case of resistance or contraindications to conventional treatments. AIM To document the presence of BRAF V600E and additional mutations, their behavior, and targeted therapies in these tumors. METHODS An electronic literature search was conducted according to PRISMA guidelines in PubMed/MEDLINE, Cochrane, EMBASE, and SpringerLink using the terms "ameloblastomas", "BRAF V600E", "additional mutations", and "targeted therapies". Ameloblastomas were classified according to WHO guidelines. Inclusion criteria were articles in English, published not more than 10 years ago, and studies with laboratory works related to BRAF V600E. Articles were evaluated by two independent reviewers and retrieved for full-text evaluation. The EBLIP Critical Appraisal Checklist was used to evaluate the quality of the eligible studies. Descriptive statistical analysis was performed. RESULTS Two independent reviewers, with a substantial concordance indicated by a kappa coefficient of k = 0.76, evaluated a total of 19 articles that were included in this study. The analysis registered 521 conventional ameloblastomas (AM), 81 unicystic ameloblastomas (UA), 13 ameloblastic carcinomas (AC), three metastatic ameloblastomas (MA), and six peripheral ameloblastomas (PA), of which the histopathological type, anatomic location, laboratory tests, expression of BRAF mutation, and additional mutations were registered. The BRAF V600E mutation was found in 297 AM (57%), 63 UA (77.7%), 3 AC (23%), 1 MA (50%), and 5 PA (83.3%). Follicular type predominated with a total of 116 cases (40%), followed by plexiform type with 63 cases (22.1%). Furthermore, both types presented additional mutations, in which alterations in JAK3 P132T, SMARCB1, PIK3CA, CTNNB1, SMO, and BRAF G606E genes were found. Four case reports were found with targeted therapy to BRAF V600E. CONCLUSION The identification of BRAF V600E and additional mutations as an aid in targeted therapies has been a breakthrough in alternative treatments of ameloblastomas where surgical treatments are contraindicated.
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Affiliation(s)
- Rogelio González-González
- Department of Research, School of Dentistry, Universidad Juárez del Estado de Durango, Durango 34000, Mexico
| | - Sandra López-Verdín
- Research Institute of Dentistry, Health Science Center, Universidad de Guadalajara, Guadalajara 4430, Mexico
| | - Jesús Lavalle-Carrasco
- Department of Research, School of Dentistry, Universidad Juárez del Estado de Durango, Durango 34000, Mexico
| | - Nelly Molina-Frechero
- Department of Health Care, Xochimilco Unit, Universidad Autónoma Metropolitana Xochimilco, México 04960, Mexico
| | - Mario Isiordia-Espinoza
- Department of Clinics, Biomedical Sciences Division, Centro Universitario de los Altos, Universidad de Guadalajara, Tepetitlán de Morelos 47620, Mexico
| | - Ramón G Carreón-Burciaga
- Department of Research, School of Dentistry, Universidad Juárez del Estado de Durango, Durango 34000, Mexico
| | - Ronell Bologna-Molina
- Molecular Pathology Area, School of Dentistry, Universidad de la República, Montevideo 11600, Uruguay
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