Incidence Of BRAF V600E Mutation Research Articles

BRAF V600E mutation mediates invasive and growth features in ameloblastoma.

Ameloblastoma (AM), a locally aggressive tumor with extensive growth capacity, causes significant damage to the jaw and affects facial appearance. Although the high prevalence of BRAF V600E mutation in AM is known, its specific impacts on patients with AM remain unclear. Thus, the present study investigated the role of BRAF V600E mutation, thereby focusing on its impact on AM invasion and growth. Immunohistochemical analysis was used to compare BRAF V600E, MMP2, MMP9, and Ki-67 expressions in AM (n = 49), normal oral mucosa (NOM) (n = 10), and odontogenic keratocyst (OKC) (n = 15) tissues. AM was further classified according to the presence or absence of BRAF V600E. The relationship between BRAF V600E and invasion as well as growth was evaluated. In addition, correlation analysis was performed using immunohistochemistry and confirmed via double-labeling immunofluorescence. Finally, comparative analyses using mass spectrometry, immunohistochemistry, and immunofluorescence were performed to explore and identify underlying mechanisms. AM exhibited a higher incidence of BRAF V600E mutation than NOM and OKC. BRAF V600E expression was positively correlated with the invasion-associated proteins MMP2 and MMP9 and the growth-related protein Ki-67. Proteomic data revealed that BRAF V600E primarily activates the MAPK signaling pathway in AM, particularly driving the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). In summary, the findings suggested that the BRAF V600E mutation enhances the invasion and growth abilities of AM via the MAPK/ERK signaling pathway. Thus, targeting BRAF V600E or the MAPK/ERK pathway may be a potential AM therapy.

Prevalence and impact of non-alcoholic fatty liver disease in patients with papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) is the most common thyroid cancer. Non-alcoholic Fatty Liver Disease (NAFLD) was possibly among the risk factors for thyroid carcinoma. It is uncertain whether NAFLD is associated with the aggressiveness of PTC. We obtained data on patients with PTC who had undergone surgery at the First Affiliated Hospital of Wenzhou Medical University between January 2020 and February 2022. Pre-and post-operative data were obtained from electronic medical records and analyzed. Patients were split into two groups based on the NAFLD diagnostic criteria and compared using univariate and multivariate analysis through a logistic regression model. In all, 3468 patients with PTC were included in this study, of which 594 (17.1%) were diagnosed with NAFLD. NAFLD was found to be an independent risk factor for lymph node metastasis (OR = 1.285 95% CI: 1.052-1.570), incidence of BRAF V600E mutation (OR = 1.504, 95% CI: 1.148-1.972) and later tumor stage at diagnosis (OR = 2.310, 95% CI: 1.700-3.139) in PTC. The association mentioned above remained significant in subgroups of patients with Hashimoto's thyroiditis (HT), hypertension, diabetes (DM), high triglyceride (TG) levels, low levels of high-density lipoprotein-cholesterol (HDL-C), and high body mass index (BMI). In subgroup of female rather than male, NAFLD was an independent risk factor for lymph node metastasis (OR = 1.638 95% CI: 1.264-2.123), incidence of BRAF V600E mutation (OR = 1.973, 95% CI: 1.368-2.846) as well as later tumor stage (OR = 2.825, 95% CI: 1.964-4.063) in PTC. However, NAFLD was not a risk factor for the larger tumor size (>1 cm), extra-thyroidal extension (ETE), or multifocality in PTC. Our cross-sectional study indicated that there is a strong association of NAFLD with higher incidence of lymph node metastasis, higher incidence of BRAF V600E mutation and later TNM stage than non-NAFLD in females with PTC.

Selection Strategies and Practical Application of BRAF V600E-Mutated Non-Small Cell Lung Carcinoma.

PurposeThe incidence of BRAF V600E mutation in non–small cell lung carcinoma (NSCLC) is lower than 2%, which poses difficulties in finding legitimate patients for targeted therapy. We investigated the predictive factors pertaining to BRAF V600E and the effectiveness of the VE1 antibody as a screening method for patient selection.Materials and MethodsThe study was designed into two steps. In a first group, BRAF-mutated NSCLCs were identified from sequencing data to determine the features of BRAF V600E mutation. The results of the first group helped the collection of adenocarcinomas with a papillary or micropapillary pattern but without epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) alterations as a second group so that the frequency of BRAF V600E mutation could be calculated. The sensitivity and specificity of the VE1 were compared with BRAF V600E status.ResultsAmong 39 BRAF-mutated NSCLCs in the first group, 20 (51%) were V600E. BRAF V600E mutation was more common in female patients and showed no significant correlation with smoking status. Nineteen cases were adenocarcinomas without EGFR and ALK alterations. The most common patterns of invasion were papillary and micropapillary along with central fibrosis. The sensitivity and specificity of the VE1 were 90.0% and 92.3%, respectively. In the second group, 6.7% of cases were VE1-positive, indicating that the prevalence was significantly higher than that reported in previous studies (0.3%–1.8%).ConclusionBRAF V600E-mutated NSCLCs could be enriched with the application of clinicopathologic parameters, which are not perfect. Therefore, additional VE1 immunohistochemistry may be useful as a screening method.

BRAF V600E mutation correlates with aggressive clinico-pathological features but does not influence tumor recurrence in papillary thyroid carcinoma-10-year single-center results.

BRAF V600E mutation is common in papillary thyroid carcinoma (PTC) but its prognostic value and influence on tumor recurrence is controversial. We investigated if BRAF V600E mutation influences tumor behavior and recurrence, and if it can be used as surrogate parameter in PTC. In a single center retrospective study with a median follow-up of 5 years, incidence of BRAF V600E mutation in 186 PTC specimens from 2007-2016 was investigated. Tumor outcome parameters including TNM status, multifocal and invasive growth and tumor recurrence rate were examined. In 98 specimens (52.7%) a BRAF V600E mutation (BRAF+), and in 88 specimens (47.3%) no mutation (BRAF-) was detected. There was no gender specific difference. BRAF+ patients were significantly older (mean 5.6 years; P=0.011). BRAF+ tumors were significantly smaller (14.4 vs. 18.3 mm; P=0.018), and more often showed a multifocal (30.6% vs. 17%; P=0.031) and extracapsular tumor growth pattern (pT3b and pT4a; BRAF+ 22.4% vs. BRAF- 10.2%; P=0.026). Although lymph node-status did not differ in both groups, BRAF+ showed a higher infiltration rate of the lateral lymph node compartment (12.2% vs. 5.7%; P=n.s.). Distant metastases occurred only in BRAF+ (3.1% vs. 0%). There was no significant difference in terms of tumor recurrence rate. Results regarding the incidence of malignant lymph nodes, tumor growth pattern and tumor multifocality suggest a more aggressive tumor behavior in BRAF+ PTC but this fact does not affect tumor recurrence rate in a five year follow up period. Therefore, the postoperative role of BRAF V600E mutation remains unclear, and a general change of operative procedure and radicality cannot be recommended based on BRAF status alone.

BRAF V600E mutations are not an oncogenic driver of solitary xanthogranuloma and reticulohistiocytoma: Testing may be useful in screening for Erdheim-Chester disease

BRAF V600E is the predominant oncogenic driver of L-group histiocytoses, which includes Erdheim-Chester disease (ECD); however, limited data exist on the prevalence of this mutation in sporadic XG family lesions. This study sought to determine the incidence of BRAF V600E mutation in a clinically annotated cohort of patients with xanthogranulomas (XG) and reticulohistiocytomas (RH). A retrospective review of 58 lesions was performed, including 41 XG and 17 RH. Immunohistochemistry (HC) and PCR-based methods were performed to evaluate for the BRAF V600E mutation. The BRAF V600E mutation was detected by IHC/PCR in 3 RH from an adult who had no history of arthritis, malignancy, xanthelasma, diabetes insipidus or bone pain. All other XG and RH were negative for the BRAF V600E mutation. No associated systemic diseases were identified in this cohort. Our findings suggest that BRAF V600E mutations are not an oncogenic driver of sporadic XG and solitary RH. Therefore, identification of such a mutation in a patient with multiple lesions should raise consideration for ECD. We also report the first known BRAF V600E mutation in a patient with multiple reticulohistiocytomas.

Association Between BRAFV600E Mutation and the American College of Radiology Thyroid Imaging, Reporting and Data System in Solitary Papillary Thyroid Carcinoma

The purpose of this study was to evaluate the associations between BRAFV600E mutation, the American College of Radiology (ACR) thyroid imaging, reporting and data system (TI-RADS) on ultrasound and clinicopathological characteristics in patients with a solitary papillary thyroid carcinoma (PTC). This retrospective study included 397 patients with a solitary PTC, proved pathologically. BRAFV600E mutation status was detected in postoperative samples by real-time fluorescent polymerase chain reaction. Associations of BRAFV600E mutation with the ACR TI-RADS and clinicopathological characteristics were analyzed. In this study, the incidence of BRAFV600E mutation was 81.4% (323/397) in patients with a solitary PTC. Univariate analyses showed that BRAFV600E mutation was significantly associated with margin, higher ACR TI-RADS point scores, and Hashimoto's thyroiditis. In multivariate analyses, lobulated or irregular margin was independently associated with BRAFV600E mutation in total solitary PTC. Furthermore, both in total solitary PTC and papillary thyroid microcarcinoma, BRAFV600E mutation was associated with ACR TI-RADS point scores, which was positively correlated with the risk of BRAFV600E mutation. There was no significant relationship between BRAFV600E mutation and ACR TI-RADS point scores in PTC >10 mm. In addition, Hashimoto's thyroiditis had a significant negative association with BRAFV600E mutation. A lobulated or irregular margin of the thyroid nodule is independently associated with BRAFV600E mutation in patients with PTC. In addition, higher ACR TI-RADS point scores is an independent risk factor for BRAFV600E mutation, and ACR TI-RADS point scores is positively associated with the risk of BRAFV600E mutation in solitary PTC, especially in papillary thyroid microcarcinoma. Our findings may be helpful for preoperative identification and medical management of PTC patients with BRAFV600E mutation.

PTPS-13STUDY OF CLINICOPATHOLOGICAL CHARACTERISTICS, BRAF V600E MUTATION, AND MTOR SIGNALING PATHWAY ACTIVATION IN DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMORS (DNET)

Dysembryoplastic Neuroepithelial Tumor (DNET) is a WHO Grade I glioneuronal tumor of children and young adults. BRAFV600E mutation has been identified in DNETs. More recently, mTOR-pathway has been implicated in molecular pathogenesis of glioneuronal tumors. We aimed to evaluate the presence of enhanced mTOR-pathway signalling, incidence of BRAFV600E mutation, and to compare the results with clinicopathological features. Immunohistochemistry for markers of mTOR-pathway activation, viz. pS6 and p4EBP1, was performed. Sequencing for BRAFV600E mutation was done in cases with adequate tissue. Sixty-seven cases of DNET were identified, accounting for 5% of patients with drug-refractory epilepsy. Mean age of patients was 16.1 years (range: 2-38 years); male preponderance was noted. Majority (68.7%) of patients were in pediatric age group (<18 years). Duration of seizures ranged from 1-22 years (mean = 7.5 years). All patients underwent ECOG-guided resection. Histopathologically, tumors were characterized by the presence of floating neurons within a specific glioneuronal element. Associated lesions such as cortical dysplasia (19%) and mesial temporal sclerosis (1.5%) were seen. Four cases were composite lesions with DNET, ganglioglioma and cortical dysplasia. pS6 immunopositivity was seen in 91% cases, while p4EBP1 was positive in 26%. Interestingly, pS6 positivity was also seen in neurons in the adjacent dysplastic cortex. Sequencing revealed BRAF V600E mutation in 11% of cases examined. Overall seizure-free survival was 87% (n = 55). Notably, of 51 patients undergoing complete resection, 48 (94%) had good outcome (Engel grade I). All four patients who underwent incomplete resection had Engel grade II-III outcomes. Thus, DNETs are rare, surgically curable neoplasms. Identification of these tumors has prognostic as well as therapeutic implications, as most patients remain seizure-free after complete resection. Evidence of mTOR-pathway activation suggests a role for mTOR signalling in their pathogenesis, and supports the use of mTOR inhibitors in DNET patients, particularly those having persistent seizures after incomplete resection.

Prognostic and Clinicopathologic Associations of BRAF Mutation in Primary Acral Lentiginous Melanoma in Korean Patients: A Preliminary Study.

BackgroundIn the majority of melanomas, the RAS/RAF/MEK/ERK signaling pathway is constitutively activated, due to oncogenic mutations in the BRAF and NRAS genes. The BRAF mutation has been mainly described in Caucasian melanomas. However, there is a lack of study evaluating the status, and the clinical significance, of BRAF mutation in the Asian population.ObjectiveThis study was aimed to determine the frequency of BRAF mutation, and to evaluate the correlation of BRAF status with clinicopathologic features and outcomes, in Korean primary acral lentiginous melanoma (ALM) patients.MethodsALM samples (n=36) were analyzed for the BRAF V600E mutation, by dual-priming oligonucleotide (DPO) based real-time polymerase chain reaction. The clinicopathologic features and prognosis of the patients were analyzed with BRAF mutation status.ResultsThe incidence of BRAF V600E mutation was 19.4% (7/36). The BRAF V600E mutations were not associated with clinicopathologic features, except for the age factor. All of the BRAF-mutant patients survived without recurrence or metastasis, and have a better clinical outcome than BRAF wild-type patients.ConclusionIn Korean primary ALM, a low frequency of BRAF mutation was shown; and BRAF mutation presented with a favorable prognosis. These results indicate that other distinctive genetic mechanisms may have more important roles in the development and progression of disease. Further multicenter study with large sample size is firmly needed, to confirm the results of our preliminary study.

Abstract 23: Low incidence of BRAFV600E mutation among melanoma patients in Ireland.

Abstract Background: Aberrant activity of the mitogen-activated protein kinase (MAPK) signalling pathway represents a critical factor in the initiation and development of melanoma. Activation can be the result of largely mutually exclusive somatic mutations of KIT, NRAS, or more frequently, BRAF(V600E). The FDA and EMA approval of a BRAF inhibitor (vemurafenib) that blocks the function of the BRAFV600E protein established a new paradigm for targeted drug development. Currently, BRAF inhibitors are one of the most promising approaches to treat metastatic melanoma. Methods: In this study, we applied mass spectrometry-based SNP genotyping (Sequenom) to detect single nucleotide mutations in 33 cancer-related genes including BRAF, NRAS, KIT, CTNNB1, GNAS, and MET. PCR and extension primers for the multiplexed assay were designed with the Sequenom Assay Design software. Samples were processed as recommended by the manufacturer. Matrix chips were assayed on a Sequenom MassArray MALDI-TOF Mass Array system. Visual inspection and Sequenom Typer software were used to perform genotyping based on mass spectra. We compared two independent melanoma cohorts, one from Ireland (SVUH cohort; n=97) and the other from Belgium (Leuven cohort; n=60). Results: Intriguingly, patients from Ireland showed significant lower BRAFV600E mutation rates (19.0%) when compared to the mutation frequency seen with the Belgian cohort (43.3%) or with the mutation frequency reported by other studies on non-Irish populations (50-70%). In addition, BRAFV600K mutation is rare in the SVUH cohort (1.0%) compared with the Leuven cohort (6.7%). Mutations in BRAFV600M and V600R were &amp;lt;2% in both groups. Although the number of NRASQ61 mutant cases was slightly higher among the Irish melanoma patients compared with Belgium patients (20.6% and 13.3%, respectively), this does not fully account for the difference in BRAFV600E mutation rate. In contrast, many BRAFV600 WT patients in the SVUH cohort carried significantly increased mutation rates in MET (11.4%) compared to the Leuven cohort (0%) and reported elsewhere (2%). c-MET is a receptor tyrosine kinase that activates multiple signal transduction pathways, including MAPK, PI3K, WNT, and Notch. MET inhibitors that are currently in clinical trials include cabozantinib and foretinib and might be a valuable alternative treatment strategy for patients exhibiting this mutation. Mutation rates of the other examined genes were always &amp;lt;5% and did not significantly differ between the groups. Conclusion: Our observation of reduced BRAFV600E mutation rates in Irish patients will directly impact future treatment strategies for these patients. The identification of substantial mutation rates in MET opens up opportunities for targeting a significant subset of melanoma patients with MET inhibitors. Citation Format: Balazs Balint, Karin van den Hurk, Sinead Toomey, Louise Unwin, Kieran Sheahan, Enda McDermott, Ian Murphy, Joost van den Oord, Mairin Rafferty, Bryan Hennessy, William M. Gallagher. Low incidence of BRAFV600E mutation among melanoma patients in Ireland. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 23. doi:10.1158/1538-7445.AM2013-23

Determination of the BRAF V600E mutation in Uruguayan melanoma patients.

e19007 Background: Vemurafenib approval by the FDA determines a new era for the treatment of metastatic melanoma in those patients with BRAF V600E mutation. This mutation is reported in about 50% of melanomas and is more common in melanomas on skin without chronic sun induced damage. The aim of this study was to evaluate the frequency of BRAF V600E mutation in Uruguayan melanoma patients, in order to analyze whether the use of vemurafenib would impact on our population. Methods: Formalin fixed, paraffin embedded tissues from 27 primary cutaneous melanomas, were obtained from files of the the Dermatopathology Unit, Department of Dermatology, Hospital de Clínicas in Montevideo, Uruguay. Most were Superficial Spreading Melanomas from skin without chronic sun induced damage. Microdissection of melanoma cells from paraffin embedded tissue was performed under microscopic visualization using a micromanipulator equipment. ADN extraction was performed and the BRAF V600E was detected by ASO-PCR. Results: Of the 27 melanoma samples analyzed, we detected the BRAF V600E mutation in 21. This determines a 77.8% frequency of mutation, a higher percentage than reported in the literature. This could be explained in different ways. The demographic characteristics of Uruguayan population are very peculiar, complying with a genetic admixture of Europeans(mostly from Spain), Amerindians (10%) and alow percentage of Africans (6%), which could explain the high incidence of BRAF V600E mutation. On the other hand, these melanomas were from skin without chronic sun induced damage, this type of melanomas have the highest rate of mutation. Finally, this mutation was analyzed in samples microdissected from melanoma biopsies, the fact that the cells were precisely removed from the tumor could also explain the high frequency of mutation. Conclusions: In this study we found a high frequency of BRAF V600E mutation in Uruguayan malignant melanoma patients, this could be explained by population genetic admixture, the melanoma subtype or technical characteristics. Further studies comparing techniques should be performed in our country to clarify this point.

BRAFV600E mutation does not serve as a prognostic factor in Korean patients with papillary thyroid carcinoma

In recent years, BRAF(V600E) mutation has emerged as a promising prognostic marker for risk stratification of patients with papillary thyroid carcinoma (PTC). However, routine use of this marker has been questioned. In some parts of the world, particularly in Korea, the incidence of BRAF(V600E) mutation is too high to have true prognostic value. The relatively low number of tumors without BRAF(V600E) mutation would prejudice the efficient use of this marker in the Korean population. The study involved 107 patients with histologically confirmed conventional PTC after surgical management for thyroid cancer from April 2010 to December 2010. BRAF(V600E) mutation analysis was performed by polymerase chain reaction (PCR)-based amplification of DNA extracted from paraffin-embedded tumor specimens, and the relationship between BRAF(V600E) mutation and various prognostic factors was investigated. BRAF(V600E) mutation was found to be present in 85 (79.4%) of 107 patients with conventional PTC. Analysis of the clinical characteristics as function of the presence or absence of BRAF(V600E) mutation revealed no differences between the BRAF(V600E)-positive and BRAF(V600E)-negative patients. Moreover, BRAF(V600E) mutation was not correlated with any of the prognostic factors including age ≥45 years, male gender, tumor size ≥1cm, multifocality, extra-thyroidal extension, concurrent Hashimoto's thyroiditis, and lymph node metastasis neither in the univariate nor in the multivariate analysis. BRAF(V600E) mutation does not significantly reflect tumor aggressiveness in Korean patients with conventional PTC. We consider that BRAF(V600E) mutation does not possess prognostic value in Korea, where it is prevalent, and where most of the PTC types are conventional.

Microsatellite Instability, Mismatch Repair Deficiency, and BRAF Mutation in Treatment-Resistant Germ Cell Tumors

Mismatch repair (MMR) deficiency and microsatellite instability (MSI) are associated with cisplatin resistance in human germ cell tumors (GCTs). BRAF mutation (V600E) is found in MSI colorectal cancers. The role of RAS/RAF pathway mutations in GCT treatment response is unknown. Two patient cohorts were investigated: 100 control GCTs (50 seminomas and 50 nonseminomas) and 35 cisplatin-based chemotherapy-resistant GCTs. MMR proteins were analyzed by immunohistochemistry, and eight microsatellite loci were examined for MSI. Tumors were assessed for specific BRAF and KRAS mutations. Resistant tumors showed a higher incidence of MSI than controls: 26% versus 0% in two or more loci (P < .0001). All resistant tumors were wild-type KRAS, and two controls (2%) contained a KRAS mutation. There was a significantly higher incidence of BRAF V600E mutation in resistant tumors compared with controls: 26% versus 1% (P < .0001). BRAF mutations were highly correlated with MSI (P = .006), and MSI and mutated BRAF were correlated with weak or absent staining for hMLH1 (P = .017 and P = .008). Low or absent staining of hMLH1 was correlated with promoter hypermethylation (P < .001). Tumors lacking expression of hMLH1 or MSH6 were significantly more frequent in resistant GCTs than in controls (P = .001 and 0.0036, respectively). Within the subgroup of resistant tumors, patients with MSI showed a trend to longer progression-free survival (P = .068). We report for the first time a correlation between a gene mutation--BRAF V600E--and cisplatin resistance in nonseminomatous GCTs. Furthermore, a correlation between MMR deficiency, MSI, and treatment failure is confirmed.