Identification of recurrent SMO and BRAF mutations in ameloblastomas

Sweeney, Robert T.; McClary, Andrew C.; Myers, Benjamin R.; Biscocho, Jewison; Neahring, Lila; Kwei, Kevin; Qu, Kunbin; Gong, Xue; Ng, Tony; Jones, Carol D.; Varma, Sushama; Odegaard, Justin I.; Sugiyama, Toshihiro; Koyota, Souichi; Rubin, Brian P.; Troxell, Megan L.; Pelham, Robert J.; Zehnder, James L.; Beachy, Philip A.; Pollack, Jonathan R.; West, Robert B.

doi:10.1038/ng.2986

Cited by 297 publications

(467 citation statements)

References 35 publications

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“…These mutations have been reported in BCC (12)(13)(14)(15)(16), a subpopulation of medulloblastoma (17,18), meningiomas without NF2 mutations (19,20), and ameloblastomas (21). Variants in PTCH1 are found in other cancers, such as ovarian and endometrial (http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/), however, their relevance to these diseases is not established.…”

Section: Ligand-independentmentioning

confidence: 99%

Efficacy of Hedgehog Pathway Inhibitors in Basal Cell Carcinoma

Basset-Séguin

Sharpe

Sauvage

2015

Molecular Cancer Therapeutics

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Basal cell carcinoma (BCC) is the most commonly diagnosed cancer. While most BCCs are amenable to surgery, some tumors can reach a more advanced stage or metastasize, and become ineligible for surgical resection or radiotherapy. Abnormal activation of the Hedgehog (Hh) pathway is a key driver in BCC pathophysiology. Consequently, inhibitors of the Hh pathway have been developed. Molecules that inhibit the receptor protein Smoothened (SMO) are the most advanced in clinical development. Vismodegib is the first-in-class SMO inhibitor and has been approved in a number of countries for the treatment of metastatic or locally advanced BCC. Several molecules have demonstrated antitumoral activity, but treatment may be limited in duration by a number of side effects, and it is not yet established whether these agents are truly curative or whether continued treatment will be required. Resistance to SMO inhibition has been reported in the clinic for which incidence and mechanisms must be elucidated to inform future therapeutic strategies. Intermittent dosing regimens to improve tolerability, as well as neoadjuvant use of Hh pathway inhibitors, are currently under investigation. Here, we review the most recent outcomes obtained with Hh inhibitors under clinical investigation in BCC.

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Section: Ligand-independentmentioning

confidence: 99%

Efficacy of Hedgehog Pathway Inhibitors in Basal Cell Carcinoma

Basset-Séguin

Sharpe

Sauvage

2015

Molecular Cancer Therapeutics

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“…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

“…Já em ameloblastomas, o fator de crescimento epidérmico e o receptor de fator crescimento fibroblástico 2 se encontram especialmente aumentados (Brown et al, 2014;Kurppa et al 2014;Sweeney et al, 2014). A ativação desses receptores com os seus ligantes ocorrem no meio extracelular e uma vez ativados fora da célula, esses receptores contribuem para ativação das vias intracelulares.…”

Section: Revisão De Literaturaunclassified

“…A ativação desses receptores com os seus ligantes ocorrem no meio extracelular e uma vez ativados fora da célula, esses receptores contribuem para ativação das vias intracelulares. Então, a via de proteínas quinases ativadas por mitógeno (Ras/MAPK) são ativadas sequencialmente em cadeia e outras proteínas da via intracelular como a quinase específica para serina/treonina (RAF) e BRAF também se tornam ativas (Brown et al, 2014;Sweeney et al, 2014).…”

Section: Revisão De Literaturaunclassified

“…Com relação a presença desse oncogene, foi demonstrado uma frequência que varia de 46 a 82% dos casos de ameloblastomas (Brown et al, 2014;Kurppa et al, 2014;Sweeney et al, 2014;Fregnani et al, 2017).…”

Section: Radiográficosunclassified

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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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Fibroblasts promote the collective invasion of ameloblastoma tumor cells in a 3D coculture model

et al. 2017

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Ameloblastoma is a benign tumor of the odontogenic epithelium with several histological subtypes. All subtypes of ameloblastoma contain abundant stroma; the tumor cells invade collectively into the surrounding tissues without losing intratumor cell attachments. However, the molecular mechanisms mediating ameloblastoma invasion remain unclear. Here, we evaluated the functional significance of the interactions between ameloblastoma tumor cells and stromal fibroblasts on collective cellular invasion using a three‐dimensional cultivation method, double‐layered collagen gel hemisphere ( DL ‐ CGH ) culture. The AM ‐1 plexiform and AM ‐3 follicular human ameloblastoma cell lines and HFF ‐2 human fibroblasts were labeled with GFP and DsRed, respectively. Collective cellular invasion of ameloblastoma cells was assessed in the presence or absence of fibroblasts. Notably, without fibroblasts, AM ‐1 cells formed sharp, plexiform‐like invasive processes, whereas AM ‐3 cells formed a series of blunt processes often observed during collective migration. In comparison, under the cocultures with HFF ‐2 fibroblasts, AM ‐3 cells formed tuft‐like invasive processes and collectively invaded into outer layer more than that observed with AM ‐1 cells. Moreover, HFF ‐2 fibroblasts localized to the tips of the invasive tumor processes. These findings suggest that tumor‐associated cells assist tumor cell invasion. Microscopic analysis of sectioned three‐dimensional cultures revealed that AM ‐3/ HFF ‐2 hemispheres were histologically similar to follicular ameloblastoma tumor samples. Therefore, our findings suggest that ameloblastoma subtypes exhibit distinct invasion patterns and that fibroblasts promote collective tumor invasion in follicular ameloblastoma.

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Identification of recurrent SMO and BRAF mutations in ameloblastomas

Cited by 297 publications

References 35 publications

Efficacy of Hedgehog Pathway Inhibitors in Basal Cell Carcinoma

Efficacy of Hedgehog Pathway Inhibitors in Basal Cell Carcinoma

Análise imunohistoquímica da mutação BRAF V600E em ameloblastomas mandibulares

Fibroblasts promote the collective invasion of ameloblastoma tumor cells in a 3D coculture model

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