scholarly journals BRAF Mutation (V600E) Prevalence in Mexican Patients Diagnosed with Melanoma

2016 ◽  
Vol 9 (1) ◽  
pp. 241-245 ◽  
Author(s):  
Priscilla Denise Zepeda-Lopez ◽  
Julio Cesar Salas-Alanis ◽  
Sonia Toussaint-Caire ◽  
Daniela Gutierrez-Mendoza ◽  
Elisa Vega-Memije ◽  
...  

Background: B-Raf is a serine/threonine protein kinase activating the MAP kinase/ERK-signaling pathway. It has been shown that 50% of melanomas harbor activating BRAF mutations, with over 90% being the V600E mutation. Objective: The goal of this research was to determine the prevalence of the BRAF V600E mutation in patients from Central Mexico diagnosed with primary melanoma. Methods: Skin biopsies from 47 patients with melanoma were obtained from the dermatology department of the Hospital General ‘Dr. Manuel Gea González' in Mexico City. For BRAF mutation determination, after DNA isolation, the gene region where the mutation occurs was amplified by PCR. Subsequently, the presence or absence of the V600E mutation was detected by Sanger sequencing performed at the private molecular diagnostic laboratory Vitagénesis in Monterrey, Mexico. Results: Of the 47 patients sampled, 6.4% harbored the V600E mutation. No statistical significance was found between mutations and the type of tumor.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11086-11086
Author(s):  
Helen J. Huang ◽  
Benoit Devogelaere ◽  
Gerald Steven Falchook ◽  
Siqing Fu ◽  
Laura S. Angelo ◽  
...  

11086 Background: Mutations in the BRAF gene provide actionable targets for cancer therapy in melanoma and other tumor types. Novel, fast, and accurate diagnostic systems are needed for further implementation of personalized therapy. Methods: The molecular diagnostics (MDx) prototype platform (Biocartis, Mechelen, Belgium) is a fully integrated real-time PCR-based system with high sensitivity (1% mutant in wild-type [wt] background) and fast turnaround time (< 90 minutes), which requires no sample preparation and <2 min hands-on time. Archival formalin-fixed paraffin-embedded tumor samples (1 to 5 shavings of 10 µm) from patients (pts) with advanced cancers previously tested for V600 BRAF mutations in a CLIA-certified Molecular Diagnostic Laboratory (PCR-based sequencing or Sequenom MassARRAY) were tested for BRAF V600 mutations using the MDx prototype platform. Concordance between methods and treatment outcomes with BRAF/MEK inhibitors were analyzed. Results: Forty-seven pts (melanoma, n=26; colorectal, n=8; papillary thyroid, n=3; other cancers, n=10) with available tissue and CLIA laboratory BRAF results were selected (BRAF V600 mutant, n=37; BRAF V600 wt, n=10). Of the 40 pts for whom the same tissue block was used for MDx and CLIA, BRAF status was concordant in 38 (95%; kappa 0.87; 95% CI 0.69-1.05) of them. BRAF status by MDx was discordant with CLIA in 3 of 47 cases (mutant by CLIA, but not MDx); one discrepant case contained a different mutation subtype (resp. V600E vs. V600K/R), and in another case different tissue blocks were used for MDx vs. CLIA testing. Of 34 pts with BRAF mutations detected by MDx, 28 were treated on protocols (on the basis of the CLIA results) with BRAF/MEK inhibitors and 8 (29%) had a partial (n=7) or complete response (n=1). Of interest, 1 pt with prostate cancer (V600E by CLIA, wt by MDx) received a BRAF/MEK inhibitor and did not respond. Detailed patient characteristics, mutation types and discrepancy analysis will be presented. Conclusions: The BRAF V600 mutation MDx prototype assay is a fast (turn-around time about 1.5 hours) and simple (<2 minutes hands-on time) test to determine BRAF mutation status with 95% concordance with CLIA laboratory if identical tissue blocks are used.


2009 ◽  
Vol 27 (13) ◽  
pp. 2129-2136 ◽  
Author(s):  
Friedemann Honecker ◽  
Hendrik Wermann ◽  
Frank Mayer ◽  
Ad J.M. Gillis ◽  
Hans Stoop ◽  
...  

Purpose 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. Patients and Methods 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. Results 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). Conclusion 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.


2015 ◽  
Vol 4 (2) ◽  
pp. 12-30 ◽  
Author(s):  
Niki Margari ◽  
Abraham Pouliakis ◽  
Aris Spathis ◽  
Emmanouil Mastorakis ◽  
Efthymios Karakostas ◽  
...  

The assessment of BRAF V600E mutations is important for prognosis and treatment of Papillary Thyroid Carcinomas (PTC), the standard methods for their identification are molecular biology techniques. In this study, the potential of image morphometry applied to cell nuclei and sequentially the use of a Classification And Regression Tree (CART) is investigated, in order to: identify morphometric features useful to characterize BRAF mutations, and to eventually produce an algorithm identifying BRAF mutation status. The 140 studied cases had histological confirmation and known BRAF mutation status identified via real-time PCR. The analysis revealed that nuclear features contributing to BRAF mutation status identification via the CART model are related mostly to nuclear color. According to the results there is evidence that BRAF V600E mutations can be identified by measurable image features. Therefore, the proposed method is useful for quality control of BRAF V600E mutations on cytological slides, can serve as alternative to PCR method and may be used for remote assessment.


2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e19033-e19033
Author(s):  
Alessandra Ulivieri ◽  
Giuseppe Cardillo ◽  
Liborio Manente ◽  
Andrea Petricca Mancuso ◽  
Leonardo Vigna ◽  
...  

e19033 Background: About 25% of pts will eventually develop lung metastases from primary melanoma. Activating mutations in BRAF, NRAS, CKIT and EGFR genes are involved in melanoma progression. Trials with drugs targeting oncogenic BRAF in melanoma have shown that a V600E mutation may identify a subgroup of pts with a high response rate. Methods: We analysedtheprevalence of BRAF, NRAS and CKIT mutations by direct sequencing and of EGFR copy number alterations by FISH, in pts affected by melanoma lung metastases, and explored their correlation with lung metastasis-free survival (LMFS) and post surgical progression-free survival (psPFS). Results: Over 10 years, 33 cases of pts with melanoma lung metastases were diagnosed at our institution, of which 22 underwent surgery with curative intent. The mean age was 64 years, and 19 (57.5%) were male. 51% carried a BRAF V600E mutation while 18% had a NRAS codon 61 mutation. The two events were mutually exclusive. No alterations were observed in exon 11 of the CKIT gene. FISH analysis indicated an EGFR low amplification in 3 cases and chromosome 7 polysomy in 13 cases. The presence of a BRAF V600E mutation was associated with a longer LMFS (median 6.1 vs 4.4 years, p<0.05), but it had no impact on psPFS (26.9 vs 29.6 months, p=0.6). NRAS mutations were associated with a reduction in both LMFS (3.7 years vs 4.7 years, p = 0.008) and, more significantly, in psPFS (12,5 months vs 41,1 months, p = 0.005; hazard ratio, 2.7). Conclusions: The frequency of mutations in BRAF (51%) and NRAS (18%) observed in lung metastatic melanomas was similar to the rates reported in other metastatic sites. BRAF mutations don't appear to be related with a more aggressive clinical course, while NRAS might be an independent negative prognostic factor after resection of melanoma lung metastases. The presence of BRAF mutations should be tested in melanoma lung metastases to identify the patients eligible for anti BRAF targeted therapy.


2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e20045-e20045
Author(s):  
Joanna Vergidis ◽  
Richard John Klasa ◽  
Youwen Zhou ◽  
Elena Moon ◽  
Debbie Jepson ◽  
...  

e20045 Background: BRAF mutations are present in approximately 40-60% of cutaneous melanomas. The BRAF inhibitor vemurafenib has demonstrated dramatic anti-tumour activity in phase III trials in BRAF mutation positive (BRAFm) metastatic/unresectable melanoma; however, there is limited data outside of clinical trials. Methods: All patients > 18 years of age, PS 0-2, with metastatic/unresectable melanoma considered for treatment with vemurafenib in British Columbia between March 2011 to December 2012 were identified. CNS disease, if present, had to be radiographically stable/asymptomatic and treated with radiation and/or surgery. The BRAF V600E mutation status was evaluated centrally on primary or metastatic biopsies using a real-time PCR assay (Cobas 4800 BRAF Mutation Test, Roche Molecular Systems). Vemurafenib was initially provided through an Expanded Access Program/Roche patient assistance program and subsequently through provincial funding. Results: In total, 84 patients were identified that had undergone BRAF mutation screening, 49(58%) were BRAFm, 35(42%) were BRAFwt. For the BRAFm patients 33 have received 1 cycle of vemurafenib and are included in the present analysis (n=21 (64%) 1st line therapy; 12(36%) > 1st line therapy). BRAFm patients: median age 53 y; 64% male; PS 0/1 76%; LDH elevated 51.5%; M1c 91%; 27% history CNS metastases. With a median follow-up of 4.9 m the median PFS, measured from the 1st dose of vemurafenib, was 9 m and the median OS was 12.4 m. The 1 year PFS and OS were 47% and 50%, respectively. The median OS of patients who progressed following vemurafenib was only 2 months. There was an inferior PFS in patients with an elevated LDH (median PFS 5 m vs not reached, p=0.024) prior to receiving vemurafenib. Conclusions: The efficacy of vemurafenibin BRAF + melanoma in this population-based analysis compares favorably to estimates in the clinical trial setting. The survival of patients who progress on vemurafenib is short, highlighting the need to explore combination therapies. An updated analysis will be presented.


2021 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Elham Jamali ◽  
Ehsan Sarraf Kazerooni ◽  
Akbar Hashemi Tayer ◽  
Reza Ranjbaran

Introduction: Plasma cell leukemia (PCL) is a rare and clinically aggressive form of plasma cell dyscrasia. Despite the significant role of BRAF mutation in plasma cell neoplasms, this mutation has been rarely considered in these cases. Finding evidence guiding us toward assessing the BRAF mutation in patients with plasma cell neoplasms could help make the suitable decision for targeted therapy. Case Presentation: A 79-year-old man presented with leukocytosis. Peripheral blood smear exhibited marked lymphocytosis and infiltration of about 50% abnormal lymphoid cells with slender cell-surface projections and oval shape nucleus. These findings raised the provisional diagnosis of hairy cell leukemia (HCL) or HCL variants (HCL-v). Molecular analysis confirmed the presence of BRAFV600E mutation, which was in agreement with HCL diagnosis, albeit the flow cytometric assessment of abnormal lymphocytes corroborated PCL. Conclusions: Together with the previous comprehensive analysis regarding the association of cytoplasmic projections and BRAF mutations, our findings could suggest this morphological characteristic in plasma cells (PCs) as an indication for the assessment of BRAF V600E mutation in PC dyscrasias.


2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1599-1599
Author(s):  
Jared David Acoba ◽  
Christopher A. Lum ◽  
Lambert T Leong

1599 Background: We previously demonstrated racial disparities in colorectal cancer (CRC) survival despite adjustments for tumor and socioeconomic factors. Molecular differences in breast and lung tumors contribute to racial survival inequality, yet in CRC, molecular tumor characteristics have not been studied extensively in a racially diverse cohort. We performed a comprehensive evaluation of KRAS and BRAF mutations in a multiracial population to determine the prevalence in CRC and the degree to which these molecular traits impact survival. Methods: A retrospective cohort study of patients diagnosed with CRC between 2008 and 2011 from hospital tumor registries was performed. The prevalence of KRAS and BRAF mutations was determined for the study population and individual racial groups. Multivariable Cox proportional hazards regression models for survival were built for KRAS and BRAF mutation status while adjusting for age at diagnosis, race, and stage of disease. Results: Of 706 patients diagnosed with CRC, KRAS mutational analysis was performed on 148 subjects. 14% of subjects were white (W), 64% Asian (A), and 21% Native Hawaiian/Pacific Islander (NH). KRAS mutation was identified in 48 subjects (32%). The prevalence of mutant tumors among racial groups was W 33%, A 36%, and NH 30%. Analysis for KRAS G13D mutations revealed a prevalence of W 11%, A 9%, and NH 7%. When compared to published datasets of predominantly white patients, our multiracial cohort had a significantly higher rate of KRAS G13D mutant tumors, p=0.039. Of 74 subjects tested for the BRAF mutation, two mutant tumors were detected (3%). The prevalence of the BRAF mutation by race was 10% W, 3% A, and 0% NH (p=0.18). BRAF and KRAS G13D mutations were adverse prognostic factors in a multivariate analysis, although the odds ratios failed to meet statistical significance. Conclusions: The prevalence of BRAF and KRAS mutations in this multiracial cohort is similar to what has been previously reported. However the rates of KRAS G13D and BRAF mutant tumors in our cohort are higher than prior reports. Furthermore, KRAS G13D which has been postulated to be a favorable prognostic factor for CRC, may adversely impact survival of minority patients.


2018 ◽  
pp. 1-5
Author(s):  
Erika Ruiz-Garcia ◽  
Juan A. Matus-Santos ◽  
Jorge Alberto Guadarrama-Orozco ◽  
Miguel Angel Alvarez-Avitia ◽  
Jose Luis Aguilar-Ponce ◽  
...  

Purpose The BRAF V600E mutation has been described in melanomas occurring in the Caucasian, European, and Asian populations. However, in the Mexican population, the status and clinical significance of BRAF mutation has not been researched on a large scale. Methods Consecutive BRAF-tested Mexican patients with metastatic melanoma (n = 127) were analyzed for mutations in exon 15 of the BRAF gene in genomic DNA by real-time polymerase chain reaction technology for amplification and detection. The results were correlated with the clinical-pathologic features and the prognosis of the patients. Results The frequency of somatic mutation V600E within the BRAF gene was 54.6% (43 of 127 patients). Nodular melanoma was the most prevalent subtype in our population, with BRAF mutations in 37.2% (16 of 55 patients). In contrast, superficial spread had a frequency of 18.6% BRAF mutation (eight of 24). Other clinicopathologic features were assessed to correlate with the mutation status. Conclusion This study searched for the most prevalent BRAF V600E mutation type in melanoma in a heterogeneous population from Mexico. Nodular melanoma was found to be the most prevalent in metastatic presentation and the presence of BRAF V600E mutation, perhaps related to the mixed ancestry; in the north, ancestry is predominantly European and in the south, it is predominantly Asian. The outcomes of the mutation correlations were similar to those found in other populations.


2007 ◽  
Vol 92 (11) ◽  
pp. 4085-4090 ◽  
Author(s):  
Cristiana Lupi ◽  
Riccardo Giannini ◽  
Clara Ugolini ◽  
Agnese Proietti ◽  
Piero Berti ◽  
...  

Abstract Context: Because very few studies have examined the correlation between BRAF mutations and clinicopathological features of papillary thyroid carcinoma (PTC), we analyzed here a large and homogeneous cohort of patients with PTC for the presence of the BRAF mutation. Objective: We examined BRAF mutations in a consecutive series of 500 PTC patients who underwent surgery in the Department of Surgery of the University of Pisa, and we correlated the presence of the mutation with clinicopathological parameters of the patients: age, gender, tumor size, presence of tumor capsule, extrathyroidal invasion, multicentricity, presence of node metastases, and tumor class. Design: BRAF (exon 15) mutation was examined by PCR-single strand conformational polymorphism followed by DNA sequencing in laser-capture microdissected tissue samples. Results: In this study, BRAF mutation was found in 219 of 500 cases (43.8%). In particular, we found the most common BRAF V600E mutation in 214 cases (42.8%), BRAF K601E mutation in three cases (0.6%), BRAF VK600–1E (0.2%) in one case, whereas in one case we found a new 14-bp deletion with concomitant 2-bp insertion, VKSR600–3del and T599I, respectively. BRAF V600E was associated with extrathyroidal invasion (P &lt; 0.0001), multicentricity (P = 0.0026), presence of nodal metastases (P = 0.0009), class III vs. classes I and II (P &lt; 0.00000006), and absence of tumor capsule (P &lt; 0.0001), in particular in follicular- and micro-PTC variants. By multivariate analysis, the absence of tumor capsule remained the only parameter associated (P = 0.0005) with BRAF V600E mutation. Conclusions: Our data suggest that BRAF V600E mutation is associated with high-risk PTC and in particular in follicular variant with invasive tumor growth.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5638-5638
Author(s):  
Alina Danu ◽  
Sophie Cotteret ◽  
Ludovic Lacroix ◽  
Véronique Saada ◽  
Véronique Vergé ◽  
...  

Abstract Background: The oncogenic BRAF V600E mutation activates the MAPK signaling pathway resulting in cell growth and survival of tumor cells carrying the mutation. Targeting BRAF has shown its efficacy in metastatic melanomas. BRAF V600E mutation has been described in multiple myeloma (MM), with an incidence of 4-10% in previous reports. We report here the incidence of BRAF mutations in a series of MM patients treated at our center. Methods: From February 2012 to March 2016, 94 MM patients were tested for BRAF mutations. Eighty-one samples came from patients with relapsed/refractory MM (R/R MM) and 13 samples from newly diagnosed patients. Eighty-eight samples were collected from bone marrow aspirates, 3 from extramedullary plasmacytoma biopsies, 1 from pleural effusion, and 2 from peripheral blood. Targeted sequencing for BRAF mutations using Sanger direct sequencing or targeted next generation sequencing were performed on all samples after CD138 cell (after 2015). In addition, NGS was performed for 2 patients. From 2012 to 2015, we used material obtained from scraping bone marrow smears with > 20% plasma cells. Since 2015, we began using immunomagnetic cell-sorting based on the CD138 cell surface marker (Stem Cells®). Results: BRAF mutations were detected in 8 samples out of the 84 that could have been screened (9.5%). When considering only the relapsed/refractory population, the incidence of BRAF mutations was 10.8%. One sample had the inactivating D594N BRAF mutation and the other 7 had the V600E BRAF mutation. The 8 mutated patients had relapsed/refractory MM at the time of analysis. Of note, 5 out of the 8 mutated patients (62.5%) had an IgA MM. Seventy-six samples had no BRAF mutation detectable. Ten samples were not tested because of the small percentage of MM cells on the bone marrow smears. The failure rate was 16% with the scraping technique and 3.4% with the sorting cell technique. Five out of 7 patients harboring the V600E BRAF mutation were treated with a BRAF inhibitor in different clinical trials. One mutated patient could not be treated due to exclusion criteria related to an underlying condition (terminal renal failure requiring chronic hemodialysis) and one patient received allogeneic stem-cell transplantation at relapse. No BRAF mutation was detected in the 13 newly diagnosed patients. Conclusion: Our results show that BRAF screening is feasible in routine practice and can help orienting therapy in relapsed/refractory MM patients. The incidence of 9.5% that we found in our series compares favorably with previously published results, and we observed a slightly increased incidence of 10.8% in the R/R population. The cell sorting technique seems to be more effective than the scraping technique for MM sample DNA acquisition and BRAF mutation screening. Results of BRAF inhibitors therapy in MM are eagerly awaited. Disclosures Lacroix: sanofi: Research Funding; qiagen: Membership on an entity's Board of Directors or advisory committees; roche: Membership on an entity's Board of Directors or advisory committees; astrazeneca: Membership on an entity's Board of Directors or advisory committees. Michot:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Ribrag:ArgenX: Research Funding; Esai: Membership on an entity's Board of Directors or advisory committees; Infinity: Membership on an entity's Board of Directors or advisory committees; Pharmamar: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; NanoString: Membership on an entity's Board of Directors or advisory committees.


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