Detection of MAPK/ERK pathway proteins and KRAS mutations in adenomatoid odontogenic tumors

Bologna‐Molina, Ronell; Ogawa, Ikuko; Mosqueda‐Taylor, Adalberto; Takata, Takashi; Sánchez‐Romero, Celeste; Dorrego, Mariana Villarroel; Takeda, Yasunori; Mikami, Taisei

doi:10.1111/odi.12989

Cited by 19 publications

(21 citation statements)

References 39 publications

(66 reference statements)

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“…Interestingly, the proportion of AOTs with KRAS driver mutation, is similar to the proportion of driver mutations reported in ameloblastoma. Due to its high frequency, KRAS mutations were proposed as a driver mutation and signature marker of AOTs [22][23][24]. Because KRAS mutations are a recurrent finding in AOTs, Coura et al [22], suggested the presence of KRAS G12V/R to help in the diagnosis of controversial cases of AOT, in the same way that BRAF V600E could be used in routine ameloblastoma diagnostics [14,38].…”

Section: Discussionmentioning

confidence: 99%

“…Six articles reported mutations in AOT [4,[22][23][24][25][26]. A total of 59 AOTs were assessed under different genomic techniques, such as direct sequencing, targeted NGS panels, and TaqMan allele-specific qPCR (Table 1).…”

Section: Gene Mutationsmentioning

confidence: 99%

“…A total of 54 samples were analyzed among these 3 studies, from which 75.9% harbored somatic mutations in KRAS (n = 41). All the studies reported that the mutations affecting KRAS corresponded to single nucleotide variations corresponding to missense mutations [22][23][24]. All the mutations affected codon 12, in which three types of transversions were identified: guanine to thymidine (G>T) in 24/41 cases, guanine to cytosine (G>C) in 16/41 cases and guanine to an adenosine (G>A) in one case.…”

Section: Gene Mutationsmentioning

confidence: 99%

“…All the mutations affected codon 12, in which three types of transversions were identified: guanine to thymidine (G>T) in 24/41 cases, guanine to cytosine (G>C) in 16/41 cases and guanine to an adenosine (G>A) in one case. The aforementioned single base variations lead to G12V, G12R, or G12D substitutions, respectively [22][23][24] (Figures 2, 3).…”

Section: Gene Mutationsmentioning

confidence: 99%

“…However, authors have failed to show alterations in CTNNB1 [4]. Nevertheless, other more recent studies have shown consistent mutations in KRAS [22][23][24] and copy number alterations [23] affecting IGF2BP3.…”

Section: Introductionmentioning

confidence: 96%

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Genetic Profile of Adenomatoid Odontogenic Tumor and Ameloblastoma. A Systematic Review

Marín

Niklander

Martínez-Flores

2021

Front. Oral. Health

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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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Section: Discussionmentioning

confidence: 99%

Section: Gene Mutationsmentioning

confidence: 99%

Section: Gene Mutationsmentioning

confidence: 99%

Section: Gene Mutationsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

See 3 more Smart Citations

Genetic Profile of Adenomatoid Odontogenic Tumor and Ameloblastoma. A Systematic Review

Marín

Niklander

Martínez-Flores

2021

Front. Oral. Health

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Protein tyrosine phosphatases: emerging role in cancer therapy resistance

Zhao,

Shuai,

et al. 2024

Cancer Communications

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BackgroundTyrosine phosphorylation of intracellular proteins is a post‐translational modification that plays a regulatory role in signal transduction during cellular events. Dephosphorylation of signal transduction proteins caused by protein tyrosine phosphatases (PTPs) contributed their role as a convergent node to mediate cross‐talk between signaling pathways. In the context of cancer, PTP‐mediated pathways have been identified as signaling hubs that enabled cancer cells to mitigate stress induced by clinical therapy. This is achieved by the promotion of constitutive activation of growth‐stimulatory signaling pathways or modulation of the immune‐suppressive tumor microenvironment. Preclinical evidences suggested that anticancer drugs will release their greatest therapeutic potency when combined with PTP inhibitors, reversing drug resistance that was responsible for clinical failures during cancer therapy.Areas coveredThis review aimed to elaborate recent insights that supported the involvement of PTP‐mediated pathways in the development of resistance to targeted therapy and immune‐checkpoint therapy.Expert opinionThis review proposed the notion of PTP inhibition in anticancer combination therapy as a potential strategy in clinic to achieve long‐term tumor regression. Ongoing clinical trials are currently underway to assess the safety and efficacy of combination therapy in advanced‐stage tumors.

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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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Detection of MAPK/ERK pathway proteins and KRAS mutations in adenomatoid odontogenic tumors

Cited by 19 publications

References 39 publications

Genetic Profile of Adenomatoid Odontogenic Tumor and Ameloblastoma. A Systematic Review

Genetic Profile of Adenomatoid Odontogenic Tumor and Ameloblastoma. A Systematic Review

Protein tyrosine phosphatases: emerging role in cancer therapy resistance

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

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