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1.
Article in English | MEDLINE | ID: mdl-38760286

ABSTRACT

Tenosynovial giant cell tumor is a benign neoplasm arising from the synovium of joints, including the temporomandibular joint (TMJ). Despite its benign nature, these tumors may exhibit aggressive behavior. A 57-year-old woman with a swollen, hardened area in the left TMJ was referred to the university´s clinic. The diagnosis of tenosynovial giant cell tumor was made based on the presence of hyperplastic synovial lining containing mononuclear and giant cells, hemorrhagic areas, hemosiderin deposits, and calcification foci in the biopsy. A low condylectomy was performed, and histopathologic analysis of the surgical piece upheld the diagnosis. Due to histopathologic resemblance with other giant cell-rich lesions (giant cell granuloma of the jaws, brown tumor of hyperparathyroidism, and non-ossifying fibroma) for which signature mutations are known, mutational analysis of KRAS, FGFR1, and TRPV4 genes was conducted. The results revealed wild-type sequences for all the mutations tested, thereby supporting the diagnosis of tenosynovial giant cell tumor.


Subject(s)
Giant Cell Tumor of Tendon Sheath , Humans , Female , Middle Aged , Giant Cell Tumor of Tendon Sheath/pathology , Giant Cell Tumor of Tendon Sheath/genetics , Giant Cell Tumor of Tendon Sheath/surgery , Diagnosis, Differential , Biopsy , Temporomandibular Joint Disorders/pathology , Temporomandibular Joint Disorders/surgery , Temporomandibular Joint Disorders/genetics , Receptor, Fibroblast Growth Factor, Type 1/genetics , DNA Mutational Analysis , Proto-Oncogene Proteins p21(ras)
2.
Clin Case Rep ; 12(1): e8444, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38259867

ABSTRACT

Clinical Key Message: We present a case of recurring ameloblastoma in soft tissue, for which we have estimated the growth rate of the lesion. This information could help clinicians to establish follow-up protocols for the early diagnosis of recurrent ameloblastomas. Abstract: In the present paper, we present a case of recurring ameloblastoma in soft tissue, for which we have estimated the growth rate of the lesion. The area of the whole resected specimen was measured using the ImageJ guide for complex object area. After dividing the area of the recurrent tumor by the number of years during the follow-up, we found that the lesion growth rate was 5.3 cm2 per year. Although further studies are still necessary in the literature to assess the growth rate of ameloblastoma, the present report shows a different methodology to estimate it. This information could help clinicians to establish follow-up protocols for the early diagnosis of recurrent ameloblastomas.

3.
Mod Pathol ; 37(2): 100388, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37995913

ABSTRACT

Cemento-ossifying fibroma (COF) of the jaws is currently classified as a benign mesenchymal odontogenic tumor, and only targeted approaches have been used to assess its genetic alterations. A minimal proportion of COFs harbor CDC73 somatic mutations, and copy number alterations (CNAs) involving chromosomes 7 and 12 have recently been reported in a small proportion of cases. However, the genetic background of COFs remains obscure. We used a combination of whole-exome sequencing and RNA sequencing to assess somatic mutations, fusion transcripts, and CNAs in a cohort of 12 freshly collected COFs. No recurrent fusions have been identified among the 5 cases successfully analyzed by RNA sequencing, with in-frame fusions being detected in 2 cases (MARS1::GOLT1B and PARG::BMS1 in one case and NCLN::FZR1 and NFIC::SAMD1 in the other case) and no candidate fusions identified for the remaining 3 cases. No recurrent pathogenic mutations were detected in the 11 cases that had undergone whole-exome sequencing. A KRAS p.L19F missense variant was detected in one case, and 2 CDC73 deletions were detected in another case. The other variants were of uncertain significance and included variants in PC, ACTB, DOK6, HACE1, and COL1A2 and previously unreported variants in PTPN14, ATP5F1C, APOBEC1, HDAC5, ATF7IP, PARP2, and ACTR3B. The affected genes do not clearly converge on any signaling pathway. CNAs were detected in 5/11 cases (45%), with copy gains involving chromosome 12 occurring in 3/11 cases (27%). In conclusion, no recurrent fusions or pathogenic variants have been detected in the present COF cohort, with copy gains involving chromosome 12 occurring in 27% of cases.


Subject(s)
Cementoma , Fibroma, Ossifying , Odontogenic Tumors , Humans , Cementoma/pathology , Fibroma, Ossifying/genetics , Odontogenic Tumors/pathology , Genomics , Protein Tyrosine Phosphatases, Non-Receptor , Adaptor Proteins, Signal Transducing , Ubiquitin-Protein Ligases
5.
J Oral Pathol Med ; 52(7): 654-659, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37224237

ABSTRACT

BACKGROUND: Unicystic ameloblastoma is an encapsulated odontogenic neoplasm with a single cyst cavity. The conservative or aggressive surgical approaches used to treat the tumor directly affect recurrence rates. However, there is a lack of a standard protocol that can guide its management. STUDY DESIGN: We retrospectively reviewed the clinicopathological findings and therapeutical procedures of 12 unicystic ameloblastoma cases treated by the same surgeon during the past 20 years. METHODS: All cases of unicystic ameloblastoma diagnosed by biopsy and treated by the same surgeon between 2002 and 2022 were reviewed. Eligibility criteria were patients with completely filled-out charts containing the follow-up period and confirmation of the diagnoses based on the microscopic findings of the whole excised specimens. Data collected were categorized into clinical, radiographic, histological, surgical, and recurrence aspects. RESULTS: There was a female predilection (2:1), and ages ranged between 18 and 61 years (mean: 27.25, ±12.45). Almost all (92%) affected the posterior mandible. Radiographically, the mean length of the lesions was 46.14 mm ± 14.28 mm which 92% were unilocular and 8.3% multilocular. Root resorption (n = 7, 58%), tooth displacement (n = 9, 75%), and cortical perforation (n = 5, 42%) were also observed. The mural histological subtype corresponded to 9 (75%) of the cases. The same conservative protocol was performed in all cases. The follow-up period ranged between 12 and 240 months (~62 ± 65) and recurrence occurred in only one patient (8%). CONCLUSION: Our findings suggest a conservative approach should be the first option for unicystic ameloblastoma treatment, even for those with mural proliferation.


Subject(s)
Ameloblastoma , Odontogenic Tumors , Humans , Female , Adolescent , Young Adult , Adult , Middle Aged , Ameloblastoma/diagnostic imaging , Ameloblastoma/surgery , Retrospective Studies , Mandible/pathology , Biopsy
6.
Int J Dermatol ; 62(2): 154-168, 2023 Feb.
Article in English | MEDLINE | ID: mdl-35318652

ABSTRACT

Cheilitis glandularis (CG) is a rare inflammatory disease of unknown etiology that affects the minor salivary glands predominantly in the lower lip. In this article, we report the case of an 18-year-old black woman who presented with a deep suppurative type of CG in both lips. In addition, we performed a systematic literature review in five databases (PubMed, Scopus, Web of Science, Ovid, and Embase) to identify CG case reports or case series. A total of 360 references were retrieved in the electronic databases. Thirty-four articles met the inclusion criteria, and six were retrieved through manual search, totaling 40 articles included in the systematic review. Thirty-nine (68.4%) cases occurred in male individuals and 18 (31.6%) in female individuals. The mean age of affected individuals was 40.9 years. Different clinical manifestations ranging from no symptoms to discomfort, pain, swelling, erythema, eversion of the lip, dilated ductal openings, ulcers, and crust have been reported. Among the included CG cases, 41 affected exclusively the lower lip (71.9%). In four cases, the CG only affected the upper lip (7.0%). In 12 cases, the lesion affected both the lower and upper lips (21.1%). Different treatment modalities were adopted in the management of CG. Although the surgical treatment was indicated (42.1%), the conservative treatment with topical medications, as in the present case, resulted in resolution in 21.0% of cases.


Subject(s)
Cheilitis , Sialadenitis , Male , Humans , Female , Adult , Adolescent , Cheilitis/diagnosis , Sialadenitis/pathology , Lip/pathology , Salivary Glands, Minor/pathology
7.
Article in English | MEDLINE | ID: mdl-36529675

ABSTRACT

Sporadic central giant cell granulomas of the jaws (GCGJ) are often solitary lesions, characterized by KRAS, FGFR1, and TRPV4 somatic mutations. Multifocal lesions may occur and are associated with hyperparathyroidism or underlying syndromes such as cherubism, which is marked by SH3BP2 mutations, and RASopathies, which are caused by mutations in the FGFR-RAS-RAF-MEK-ERK signaling cascade. The diagnosis of multiple GCGJ can be challenging. The present case reports a 14-year-old boy with multiple central GCGJ and no obvious syndromic trait. Sanger sequencing-based analysis revealed wild-type sequences for SH3BP2 (exon 9), KRAS (exons 2-4), and FGFR1 (exons 9 and 10) genes. A rare TRPV4 somatic mutation (p.Val708Met) was detected in the lesion on the right side of the mandible, whereas the other tumor and the normal oral mucosa revealed wild-type TRPV4 sequences. This report expands the spectrum of TRPV4 somatic mutations in central GCGJ.


Subject(s)
Granuloma, Giant Cell , Male , Humans , Adolescent , Granuloma, Giant Cell/genetics , TRPV Cation Channels/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Mutation/genetics , Jaw/pathology
8.
J Hematop ; 16(4): 199-208, 2023 Dec.
Article in English | MEDLINE | ID: mdl-38175434

ABSTRACT

Follicular lymphoma is a hematolymphoid neoplasm that originates from germinal center B cells. It is made up of a combination of small cleaved centrocytes and a varying quantity of larger non-cleaved centroblasts to describe the clinical, microscopic, immunohistochemical, and molecular features of oral follicular lymphomas. Follicular lymphomas affecting the oral cavity were retrieved from pathology files. Immunohistochemistry was performed to confirm the diagnosis, and fluorescence in situ hybridization (FISH) was employed to detect rearrangements in BCL2, BCL6, and MYC genes. Clinical and follow-up data were obtained from the patient's medical and pathology files. Twenty cases were obtained. There was an equal sex distribution (10 males: 10 females) and a mean age of 60.9 years (range: 10-83 years-old). Lesions presented as asymptomatic swellings, usually in the palate (10 cases) and the buccal mucosa (7 cases). Five patients presented with concomitant nodal involvement. Microscopic evaluation depicted the follicular growth pattern with diffuse areas in six cases. Grades 1 and 2 follicular lymphomas represented 12 cases, while grade 3A neoplasms accounted for other 8 cases. Two cases showed rearrangements in MYC, BCL2, and BCL6 genes, while single BCL2 translocation was found in eight cases. Two cases had no translocation. Three patients deceased and the 2-year overall survival achieved 88%. Follicular lymphoma affecting the oral cavity is uncommon, usually affects the palate as a non-ulcerated swelling and the presence of a systemic disease most always be ruled out.


Subject(s)
Lymphoma, Follicular , Female , Male , Humans , Middle Aged , Child , Adolescent , Young Adult , Adult , Aged , Aged, 80 and over , Lymphoma, Follicular/diagnosis , In Situ Hybridization, Fluorescence , B-Lymphocytes , Germinal Center , Translocation, Genetic/genetics , Proto-Oncogene Proteins c-bcl-2/genetics
9.
Article in English | MEDLINE | ID: mdl-35153188

ABSTRACT

Adenoid ameloblastoma with dentinoid is an uncommon benign odontogenic neoplasm, and its unicystic variant seems to be even rarer. A 34-year-old man was referred for evaluation of an asymptomatic swelling in the posterior maxilla. Intraoral examination showed an expansive lesion, soft to palpation, covered by a normal color mucosa. Cone beam computed tomography revealed a well-defined unilocular hypodense tumor involving the left maxillary sinus. Histopathological examination of the surgically excised specimen showed a cystic tumor lined by an ameloblastic-like epithelium containing columnar basal cells with hyperchromatic and polarized nuclei. In some areas of the capsule, the tumor showed mural infiltration by sheets of cells containing central whirling structures. Dentinoid material was also observed in association with ameloblastic-like cells. The tumor was BRAF and KRAS wild-type. Collectively, these findings were consistent with the diagnosis of a unicystic variant of adenoid ameloblastoma with dentinoid.


Subject(s)
Adenoids , Ameloblastoma , Odontogenic Tumors , Adenoids/pathology , Adult , Ameloblastoma/diagnostic imaging , Ameloblastoma/genetics , Ameloblastoma/surgery , Epithelium/pathology , Humans , Male , Maxilla/pathology
10.
J Oral Pathol Med ; 51(2): 206-216, 2022 Feb.
Article in English | MEDLINE | ID: mdl-35048460

ABSTRACT

BACKGROUND: Central giant cell granulomas (CGCG) of the jaws are osteolytic lesions that may behave aggressively and respond poorly to surgery. Microscopically, in addition to giant cells, there is a mononuclear cell population composed of macrophage/monocytic cells and spindle-shaped cells of mesenchymal origin. Seventy two percent of these tumours harbour mutually exclusive TRPV4, KRAS and FGFR1 mutations. We aimed to assess the mutational status of mononuclear and giant cells and the osteogenic potential of stromal cells in vitro and in vivo. METHODS AND RESULTS: We screened CGCG for signature mutations and used laser-capture microdissection to demonstrate that the mutations are restricted to the mononuclear cells. Additionally, we established CGCG primary cell culture and observed that the cells retained the mutations throughout passages. By flow cytometry, we observed predominance of CD14- CD51- CD61- cells, consistent with the expected profile for stromal cells. Considering the mesenchymal origin of stromal cells, we assessed the osteogenic differentiation potential of CGCG cells in culture by cytochemistry (von Kossa and alizarin red staining), alkaline phosphatase (ALP) activity assay and gene expression of osteogenic markers. CGCG cells presented self-capacity to increase ALP levels in a time-dependent manner and under osteogenic induction presented increasing number of calcium deposits, and overall higher expression of osteocalcin, RUNX2, ALPL and osteopontin than cells without osteogenic induction. A patient-derived xenograft model for CGCG was established, and osteoid material deposition was observed. CONCLUSION: Collectively, the results confirm that the signature mutations are restricted to stromal cells in CGCG, and the in vitro and in vivo results support that these cells have the capacity to differentiate into osteoblasts, in line with the bone formation often observed in the stroma of these lesions.


Subject(s)
Granuloma, Giant Cell , Mesenchymal Stem Cells , Alkaline Phosphatase , Cell Differentiation , Cells, Cultured , Granuloma, Giant Cell/genetics , Humans , Jaw , Mutation , Osteogenesis/genetics , Stromal Cells
11.
Oral Dis ; 28(8): 2219-2229, 2022 Nov.
Article in English | MEDLINE | ID: mdl-33978981

ABSTRACT

OBJECTIVE: We aimed to assess which metabolic pathways would be implicated in the phenotypic changes of the epithelial lining of odontogenic keratocyst after marsupialization, comparing pre- and post-marsupialized lesions with adjacent oral mucosa. MATERIALS AND METHODS: Eighteen formalin-fixed and paraffin-embedded tissues from six subjects were divided into three paired groups: odontogenic keratocyst pre- (n = 6) and post-marsupialization (n = 6), and adjacent oral mucosa (n = 6). The metabolic pathways found in these groups were obtained by high-performance liquid chromatography-mass spectrometry-based untargeted metabolomics performed. RESULTS: Through putative metabolite annotation followed by pathway enrichment and predictive analysis with automated algorithms (Mummichog and Gene Set Enrichment Analysis), we found differences in many cellular processes that may be involved in inflammation, oxidative stress response, keratinocyte-basal membrane attachment, differentiation, and proliferation functions, all relevant to odontogenic keratocyst pathobiology and the phenotype acquired after marsupialization. CONCLUSION: Our study was able to identify several metabolic pathways potentially involved in the metaplastic changes induced by marsupialization of odontogenic keratocysts. An improved comprehension of this process could pave the way for the development of targeted therapies.


Subject(s)
Odontogenic Cysts , Odontogenic Tumors , Formaldehyde , Humans , Odontogenic Cysts/pathology , Odontogenic Cysts/surgery , Pilot Projects
12.
Braz Oral Res ; 35: e070, 2021.
Article in English | MEDLINE | ID: mdl-34076066

ABSTRACT

The coronavirus disease (COVID-19) has been prioritized in relation to other illnesses considered critical, such as cancer, cardiovascular diseases/stroke, diabetes, and autoimmune diseases. The management of patients with these diseases involves dental care to reduce systemic complications caused by odontogenic infections, and/or to treat oral manifestations of systemic comorbidities. In this regard, the dental care of these individuals must be guaranteed during the pandemic. Although a high risk of exposure to and catching of COVID-19 is expected to befall dental professionals, biosafety guidelines reduce the likelihood of infection. Thus, the current scenario poses challenges, and offers decision-making approaches and tools that facilitate the management of individuals with oral manifestations of chronic and/or critical diseases, using hospital-based services. This article presents an overview for hospital service providers who are at the forefront of COVID-19 care, including a secure protocol, and clinical guidelines based on the experience of the Hospital das Clínicas in Belo Horizonte, a public referral service, supported by the Brazilian National Health System.


Subject(s)
COVID-19 , Pandemics , Brazil/epidemiology , Dental Care , Hospitals , Humans , SARS-CoV-2
13.
J Oral Pathol Med ; 50(5): 478-484, 2021 May.
Article in English | MEDLINE | ID: mdl-33377543

ABSTRACT

BACKGROUND: BRAF p.V600E is reported in up to 80% of ameloblastomas. Despite the high frequency, the presence of this mutation in different histopathological areas of the tumour has not been investigated. This information has an important role in the use of BRAF p.V600E assessment as an auxiliary tool in the differential diagnosis between unicystic ameloblastoma and other odontogenic cystic lesions, especially when only incisional biopsies are available. Therefore, the purpose of the present study was to investigate BRAF p.V600E heterogeneity in unicystic ameloblastoma. METHODS: Five cases of ameloblastoma and two dentigerous cysts were analysed. The regions exhibiting different microscopic characteristics were selected from each ameloblastoma case and manually dissected. TaqMan allele-specific qPCR or Sanger sequencing was performed to determine BRAF p.V600E status. RESULTS: We screened the mutation in a small cohort of UA and no molecular heterogeneity was found. Four cases of ameloblastoma (80%) exhibited BRAF p.V600E in all different areas evaluated. One case did not harbour the mutation in any microscopic region analysed. The BRAF mutation was absent in the dentigerous cysts. CONCLUSION: Ameloblastomas appear to exhibit a homogeneous profile regarding the BRAF p.V600E no matter what histological feature is observed under light microscopy, suggesting that this molecular test may contribute to establish the correct diagnosis in cases microscopically resembling other odontogenic lesions.


Subject(s)
Ameloblastoma , Odontogenic Cysts , Ameloblastoma/diagnosis , Ameloblastoma/genetics , Diagnosis, Differential , Humans , Mutation , Proto-Oncogene Proteins B-raf/genetics
14.
Braz. oral res. (Online) ; 35: e070, 2021. tab, graf
Article in English | LILACS, BBO - Dentistry | ID: biblio-1249375

ABSTRACT

Abstract The coronavirus disease (COVID-19) has been prioritized in relation to other illnesses considered critical, such as cancer, cardiovascular diseases/stroke, diabetes, and autoimmune diseases. The management of patients with these diseases involves dental care to reduce systemic complications caused by odontogenic infections, and/or to treat oral manifestations of systemic comorbidities. In this regard, the dental care of these individuals must be guaranteed during the pandemic. Although a high risk of exposure to and catching of COVID-19 is expected to befall dental professionals, biosafety guidelines reduce the likelihood of infection. Thus, the current scenario poses challenges, and offers decision-making approaches and tools that facilitate the management of individuals with oral manifestations of chronic and/or critical diseases, using hospital-based services. This article presents an overview for hospital service providers who are at the forefront of COVID-19 care, including a secure protocol, and clinical guidelines based on the experience of the Hospital das Clínicas in Belo Horizonte, a public referral service, supported by the Brazilian National Health System.


Subject(s)
Humans , Pandemics , COVID-19 , Brazil/epidemiology , Dental Care , SARS-CoV-2 , Hospitals
15.
Oral Surg Oral Med Oral Pathol Oral Radiol ; 130(6): e328-e335, 2020 Dec.
Article in English | MEDLINE | ID: mdl-32771412

ABSTRACT

Hyaline fibromatosis syndrome (HFS) is a rare monogenic disease inherited in an autosomal recessive pattern and characterized by hyaline deposits on the skin, mucosa, and multiple organs; osteoporosis; and joint contractures. This progressive condition is caused by mutations in the gene encoding the anthrax toxin receptor 2 protein (ANTXR2). HFS is a disabling disease, and patients suffer from progressive pain and disfiguring symptoms. There are few published case reports detailing oral findings in patients with this condition. The present case report describes a 4-year-old female patient who showed severe manifestations of HFS, emphasizing the oral manifestations, the histopathologic aspects of HFS, the molecular pathogenesis, and the interdisciplinary management of patients affected by this condition.


Subject(s)
Hyaline Fibromatosis Syndrome , Child, Preschool , Female , Humans , Hyaline Fibromatosis Syndrome/diagnosis , Hyaline Fibromatosis Syndrome/genetics , Mutation , Rare Diseases , Receptors, Peptide/genetics
17.
Article in English | MEDLINE | ID: mdl-31402313

ABSTRACT

Schimmelpenning syndrome (SS) is a congenital neurocutaneous disorder characterized by the presence of linear nevus sebaceous, ophthalmic, neurologic, skeletal, urologic, and cardiovascular alterations. Oral manifestations related to SS mainly include dental defects, papillary lesions in the oral mucosa, giant cell lesions of the jaws, and odontogenic tumors. Here, we report the first case of multiple adenomatoid odontogenic tumor observed in a patient with SS.


Subject(s)
Ameloblastoma , Nevus, Sebaceous of Jadassohn , Nevus , Odontogenic Tumors , Humans
18.
Clin Oral Investig ; 24(7): 2451-2458, 2020 Jul.
Article in English | MEDLINE | ID: mdl-31713744

ABSTRACT

OBJECTIVE: Odontogenic myxoma (OM) occasionally responds poorly to surgical treatment. The MAPK pathway is constitutively activated in several neoplasms and we aimed to test if the MAPK pathway is activated in OM, in order to pave the way for an alternative therapy for aggressive and recurrent cases. MATERIALS AND METHODS: The immunoexpression of phosphorylated ERK1/2 (pERK1/2) was assessed in OM. We established a 3D organotypic culture model for the in vitro study and patient-derived xenografts (PDX) in mice for the in vivo study. The MEK inhibitor U0126 was used to inhibit phosphorylation of ERK1/2 in the in vitro and in vivo models. RESULTS: All OM showed strong pERK1/2 immunoexpression, consistent with MAPK pathway activation. Treatment of the 3D culture with U0126 resulted in a reduced pERK1/2/ERK1/2 ratio. Consistent with the in vitro results, all PDX of animals treated with U0126 showed a decreased volume fold change compared with controls. CONCLUSIONS: The MAPK pathway is activated in OM and its inhibition leads to tumor shrinkage in PDX and cell culture models. CLINICAL RELEVANCE: Our results offer a pre-clinical frame for OM-targeted therapy. Further work is needed to determine if this initial finding holds clinical promise.


Subject(s)
Mouth Diseases , Myxoma , Animals , Dual Specificity Phosphatase 1/drug effects , Humans , Mice , Mouth Diseases/drug therapy , Myxoma/drug therapy , Phosphorylation
19.
J Oral Pathol Med ; 48(2): 174-179, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30554445

ABSTRACT

BACKGROUND: Benign neoplasms exhibit most of the cellular phenomena considered hallmarks of cancer, except the capacity to metastasize. Thus, the elucidation of the mechanisms associated with the progression of benign neoplasms may complement and clarify the mechanisms involved in carcinogenesis. Benign odontogenic tumours often result in facial deformities and morbidities, and have complex pathogenesis, mainly due to the diversity of interactions between the odontogenic epithelium and the ectomesenchyme. Primary cell culture of such tumours is not only difficult to be established and maintained, but also tumour cells lose characteristic cellular morphology. Considering gene expression, growth, migration, proliferation and cellular morphology are controlled by cell-cell interactions and cell-extracellular matrix interactions, cell culture in 3D substrates has gained space as a way to overcome some of the limitations of traditional monolayer cell culture systems. METHODS: In this study, fragments obtained from mesenchymal odontogenic tumours were cultured in type I collagen scaffolds. Invasion tests were performed in these models, as well as phenotypic characterization of the cultured tumours. RESULTS: The results obtained for the odontogenic myxoma and the cemento-ossifying fibroma demonstrate a good reproduction of the growth pattern of these tumours under ex vivo conditions. Microscopic evaluation showed maintenance of cell viability in the explants for more than 30 days, without the presence of necrosis. CONCLUSION: This is the first study involving long-term 3D primary cultures of benign odontogenic tumours, which is expected to support complex approaches to cell and molecular biology, and to serve as an experimental model for testing molecular therapies.


Subject(s)
Cell Culture Techniques/methods , In Vitro Techniques , Odontogenic Tumors/pathology , Carcinogenesis , Cell Communication , Cell Movement , Cell Proliferation , Cell Survival , Cementoma , Gene Expression , Humans , Odontogenic Tumors/genetics , Tumor Cells, Cultured
20.
Nat Commun ; 9(1): 4572, 2018 11 01.
Article in English | MEDLINE | ID: mdl-30385747

ABSTRACT

Giant cell lesions of the jaw (GCLJ) are debilitating tumors of unknown origin with limited available therapies. Here, we analyze 58 sporadic samples using next generation or targeted sequencing and report somatic, heterozygous, gain-of-function mutations in KRAS, FGFR1, and p.M713V/I-TRPV4 in 72% (42/58) of GCLJ. TRPV4 p.M713V/I mutations are exclusive to central GCLJ and occur at a critical position adjacent to the cation permeable pore of the channel. Expression of TRPV4 mutants in HEK293 cells leads to increased cell death, as well as increased constitutive and stimulated channel activity, both of which can be prevented using TRPV4 antagonists. Furthermore, these mutations induce sustained activation of ERK1/2, indicating that their effects converge with that of KRAS and FGFR1 mutations on the activation of the MAPK pathway in GCLJ. Our data extend the spectrum of TRPV4 channelopathies and provide rationale for the use of TRPV4 and RAS/MAPK antagonists at the bedside in GCLJ.


Subject(s)
Giant Cell Tumor of Bone/genetics , Jaw Neoplasms/genetics , Proto-Oncogene Proteins p21(ras)/genetics , Receptor, Fibroblast Growth Factor, Type 1/genetics , TRPV Cation Channels/genetics , Adolescent , Adult , Aged , Child , Computer Simulation , Female , Gain of Function Mutation , HEK293 Cells , High-Throughput Nucleotide Sequencing , Humans , MAP Kinase Signaling System , Male , Middle Aged , Patch-Clamp Techniques , Sequence Analysis, DNA , Sequence Analysis, RNA , Exome Sequencing , Young Adult
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