Molecular dissection of the RAS/RAF/MAPK pathway in primary and metastatic melanoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8050-8050
Author(s):  
J. Rother ◽  
J. Bailey ◽  
G. Alvarado ◽  
V. G. Prieto ◽  
A. J. Lazar ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Signaling Pathway ◽  
Braf Mutation ◽  
Mapk Pathway ◽  
Point Mutations ◽  
Initial Diagnosis ◽  
Molecular Dissection ◽  
Braf Mutations ◽  
Mapk Activation ◽  
Metastatic Lesions

8050 Background: Given the reported presence of frequent mutation in NRAS and BRAF in many melanocytic lesions, the association of mutations activating the RAS/RAF/MAPK pathway with tumor progression in melanoma remains unclear. We compared the NRAS and BRAF mutation status with the levels of activated MAPK in paired primary and metastatic melanomas. Methods: 15 patients with material from both primary and metastatic lesions were assessed. Four patients had metastasis at initial diagnosis, the remaining patients developed metastasis from 8.5 to 66 months (mos) following initial diagnosis (median 24.1 mos). Mutations in BRAF (exons 11 and 15) and KRAS and NRAS (exons 1 and 2) were assessed by quantitative pyrosequencing. MAPK levels were assessed by immunohistochemistry on paraffin sections using phosphor-44/42 (Thr202/Tyr204) polyclonal antisera. Results: Activating NRAS point mutations were found in 3 of 15 patients, with 2 detected in the metastatic lesions; both of these had upregulation of activated MAPK compared to the primary lesions. BRAF V599 point mutations were found in 3 of 15 patients and present in both the primary and cognate metastatic lesions. All cases with BRAF or NRAS mutations had moderate to high levels of activated MAPK, as compared to only 2 of 9 patients without such mutations. The correlation of mutational status and clinical course revealed that NRAS/BRAF mutations and/or MAPK activation did not negatively impact overall survival. Conclusions: Molecular alterations in the RAS signaling pathway are associated with activated MAPK in both primary and metastatic melanoma. NRAS mutations and MAPK activation may be preferentially associated with disease progression, as opposed to BRAF mutations. However, neither NRAS/BRAF mutation nor activation of MAPK signaling pathway in primary and/or metastatic melanoma was significantly associated with poor disease outcome. Further molecular dissection using the archived material from two large melanoma neoadjuvant trials conducted in 1988 and 1994 is ongoing to determine the prognostic and predictive power of these biomarkers. No significant financial relationships to disclose.

scholarly journals Cutaneous Side Effects of BRAF Inhibitors in Advanced Melanoma: Review of the Literature

2016 ◽  
Vol 2016 ◽  
pp. 1-6 ◽  
Author(s):  
Bilgen Gençler ◽  
Müzeyyen Gönül
Keyword(s):  
Side Effects ◽  
Metastatic Melanoma ◽  
Mapk Pathway ◽  
Case Reports ◽  
Mitogen Activated Protein Kinase ◽  
Braf V600e ◽  
Braf Inhibitors ◽  
Braf Mutations ◽  
Cutaneous Side Effects ◽  
Downstream Signaling

The incidence of melanoma has recently been increasing. BRAF mutations have been found in 40–60% of melanomas. The increased activity of BRAF V600E leads to the activation of downstream signaling through the mitogen-activated protein kinase (MAPK) pathway, which plays a key role as a regulator of cell growth, differentiation, and survival. The use of BRAF inhibitors in metastatic melanoma with BRAF mutation ensures clinical improvement of the disease. Vemurafenib and dabrafenib are two selective BRAF inhibitors approved by the Food and Drug Administration (FDA). Both drugs are well tolerated and successfully used in clinical practice. However, some adverse reactions have been reported in patients in the course of treatment. Cutaneous side effects are the most common adverse events among them with a broad spectrum. Both the case reports and several original clinical trials reported cutaneous reactions during the treatment with BRAF inhibitors. In this review, the common cutaneous side effects of BRAF inhibitors in the treatment of metastatic melanoma with BRAF V600E mutation were reviewed.

scholarly journals Reversal of Resistance in Targeted Therapy of Metastatic Melanoma: Lessons Learned from Vemurafenib (BRAFV600E-Specific Inhibitor)

Cancers ◽  
2018 ◽  
Vol 10 (6) ◽  
pp. 157 ◽  
Author(s):  
Antoni Torres-Collado ◽  
Jeffrey Knott ◽  
Ali Jazirehi
Keyword(s):  
Metastatic Melanoma ◽  
Tumor Regression ◽  
Mapk Pathway ◽  
Specific Inhibitor ◽  
Basic Research ◽  
Underlying Mechanism ◽  
Lessons Learned ◽  
Brafv600e Mutation ◽  
Braf Mutations ◽  
Immune Resistance

Malignant melanoma is the most aggressive form of skin cancer and has a very low survival rate. Over 50% of melanomas harbor various BRAF mutations with the most common being the V600E. BRAFV600E mutation that causes constitutive activation of the MAPK pathway leading to drug-, immune-resistance, apoptosis evasion, proliferation, survival, and metastasis of melanomas. The ATP competitive BRAFV600E selective inhibitor, vemurafenib, has shown dramatic success in clinical trials; promoting tumor regression and an increase in overall survival of patients with metastatic melanoma. Regrettably, vemurafenib-resistance develops over an average of six months, which renders melanomas resistant to other therapeutic strategies. Elucidation of the underlying mechanism(s) of acquisition of vemurafenib-resistance and design of novel approaches to override resistance is the subject of intense clinical and basic research. In this review, we summarize recent developments in therapeutic approaches and clinical investigations on melanomas with BRAFV600E mutation to establish a new platform for the treatment of melanoma.

BRAF Mutation Testing in Colorectal Cancer

2010 ◽  
Vol 134 (8) ◽  
pp. 1225-1228
Author(s):  
Shree G. Sharma ◽  
Margaret L. Gulley
Keyword(s):  
Colorectal Cancer ◽  
Braf Mutation ◽  
Mapk Pathway ◽  
Growth Factor Receptor ◽  
The United States ◽  
Mutation Testing ◽  
Sporadic Colorectal Cancer ◽  
Cancer Tissue ◽  
Braf Mutations ◽  
Growth And Survival

Abstract Colorectal cancer is the second most common cause of cancer death in the United States. Understanding the biochemical pathways underlying carcinogenesis has paved the way for more effective treatments and better outcomes. BRAF mutation testing has a role in (1) differentiating sporadic colorectal cancer from Lynch syndrome, (2) identifying cancers lacking BRAF mutation that are more likely to respond to epidermal growth factor receptor inhibitor therapy, and (3) conferring worse prognosis in colorectal cancer that is microsatellite stable. Several analytic methods are available to reliably detect BRAF mutations. Real-time polymerase chain reaction identifies the most common BRAF mutation, V600E, in frozen or paraffin-embedded colorectal cancer tissue. Traditional DNA sequencing and the somewhat more-sensitive pyrosequencing method can detect multiple alternative BRAF mutations that are predicted to constitutively activate signaling through the MAPK pathway, promoting tumor growth and survival. Pathologists play an important role in assay validation as well as in consulting with clinicians about indications for testing, ensuring quality of testing, and interpreting results in conjunction with other clinicopathologic factors important in the management of affected patients.

scholarly journals Frequency of BRAF V600E Mutation in the Mexican Population of Patients With Metastatic Melanoma

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 ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Braf Mutation ◽  
Large Scale ◽  
Braf V600e Mutation ◽  
Mexican Population ◽  
Braf V600e ◽  
Braf Gene ◽  
Braf Mutations ◽  
Nodular Melanoma ◽  
Pathologic Features

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.

scholarly journals BRAF Mutations in Low-Grade Serous Ovarian Cancer and Response to BRAF Inhibition

2018 ◽  
pp. 1-14 ◽  
Author(s):  
Tania Moujaber ◽  
Dariush Etemadmoghadam ◽  
Catherine J. Kennedy ◽  
Yoke-Eng Chiew ◽  
Rosemary L. Balleine ◽  
...  
Keyword(s):  
Braf Mutation ◽  
Mapk Pathway ◽  
Braf V600e Mutation ◽  
Braf V600e ◽  
Targeted Treatment ◽  
Ca 125 ◽  
Low Grade ◽  
Tumor Type ◽  
Braf Inhibitors ◽  
Braf Mutations

Purpose Low-grade serous ovarian carcinoma (LGSC) responds poorly to chemotherapy and is characterized by activating mutations in the Ras sarcoma–mitogen-activated protein kinase (RAS-MAPK) pathway, including oncogenic BRAF. However, response to BRAF inhibitors is tumor-type specific. Significant improvement in survival is seen in patients with BRAF-mutant melanoma, but other cancer types, such as colorectal cancers, are generally less sensitive. We examined the frequency and characteristics of BRAF-mutated LGSC and described the response to treatment with BRAF inhibitors. Patients and Methods Mutations were assessed in LGSC (N = 65) by using targeted, exome, and whole-genome sequencing. Patient characteristics, treatment, and clinical outcome were assessed, and the median follow-up time was more than 5 years. BRAF inhibitors were trialed in two patients with a somatic BRAF V600E mutation: one patient received dabrafenib monotherapy and was monitored clinically, biochemically (cancer antigen [CA]-125 levels), and with positron emission tomography (PET) imaging. Expression of the BRAF V600E protein in this patient was assessed by immunohistochemistry. Results Among patients with LGSC, nine (13.8%) of 65 had a somatic BRAF mutation. Of the nine patients with BRAF mutation–positive LGSC, four experienced progressive disease that did not respond to conventional chemotherapy. Two of the patients experienced progression quickly and died as a result of disease progression, and two received targeted treatment. Two patients with BRAF V600E mutation received BRAF inhibitors at relapse and both achieved durable responses. Conclusion BRAF mutations are not uncommon in patients with LGSC and should be routinely tested, because BRAF inhibitors can be an effective treatment for these patients. The results highlight the need for targeted treatment in this rare tumor type, and a prospective study is needed to formally assess the response rate and clinical benefit.

Targeted Therapy in Advanced Melanoma With Rare BRAF Mutations

2019 ◽  
Vol 37 (33) ◽  
pp. 3142-3151 ◽  
Author(s):  
Christian Menzer ◽  
Alexander M. Menzies ◽  
Matteo S. Carlino ◽  
Irene Reijers ◽  
Emma J. Groen ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Metastatic Melanoma ◽  
Survival Data ◽  
Braf Mutation ◽  
Overall Response Rate ◽  
Response Rate ◽  
Small Sample ◽  
Braf V600e ◽  
Braf Mutations ◽  
Overall Response

PURPOSE BRAF/MEK inhibition is a standard of care for patients with BRAF V600E/K–mutated metastatic melanoma. For patients with less frequent BRAF mutations, however, efficacy data are limited. METHODS In the current study, 103 patients with metastatic melanoma with rare, activating non-V600E/K BRAF mutations that were treated with either a BRAF inhibitor (BRAFi), MEK inhibitor (MEKi), or the combination were included. BRAF mutation, patient and disease characteristics, response, and survival data were analyzed. RESULTS Fifty-eight patient tumors (56%) harbored a non-E/K V600 mutation, 38 (37%) a non-V600 mutation, and seven had both V600E and a rare BRAF mutation (7%). The most frequent mutations were V600R (43%; 44 of 103), L597P/Q/R/S (15%; 15 of 103), and K601E (11%; 11 of 103). Most patients had stage IV disease and 42% had elevated lactate dehydrogenase at BRAFi/MEKi initiation. Most patients received combined BRAFi/MEKi (58%) or BRAFi monotherapy (37%). Of the 58 patients with V600 mutations, overall response rate to BRAFi monotherapy and combination BRAFi/MEKi was 27% (six of 22) and 56% (20 of 36), respectively, whereas median progression-free survival (PFS) was 3.7 months and 8.0 months, respectively ( P = .002). Of the 38 patients with non-V600 mutations, overall response rate was 0% (zero of 15) to BRAFi, 40% (two of five) to MEKi, and 28% (five of 18) to combination treatment, with a median PFS of 1.8 months versus 3.7 months versus 3.3 months, respectively. Multivariable analyses revealed superior survival (PFS and overall survival) with combination over monotherapy in rare V600 and non-V600 mutated melanoma. CONCLUSION Patients with rare BRAF mutations can respond to targeted therapy, however, efficacy seems to be lower compared with V600E mutated melanoma. Combination BRAFi/MEKi seems to be the best regimen for both V600 and non-V600 mutations. Yet interpretation should be done with care because of the heterogeneity of patients with small sample sizes for some of the reported mutations.

Prognostic and Clinicopathologic Associations of Oncogenic BRAF in Metastatic Melanoma

2011 ◽  
Vol 29 (10) ◽  
pp. 1239-1246 ◽  
Author(s):  
Georgina V. Long ◽  
Alexander M. Menzies ◽  
Adnan M. Nagrial ◽  
Lauren E. Haydu ◽  
Anne L. Hamilton ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Distant Metastasis ◽  
Braf Mutation ◽  
Braf Inhibitor ◽  
Primary Melanoma ◽  
Age At Diagnosis ◽  
Wild Type ◽  
Braf Mutations ◽  
Mutation Status ◽  
Braf Mutant

Purpose To assess the frequency and type of oncogenic BRAF mutations in metastatic melanoma and correlate BRAF status with clinicopathologic features and outcome. Patients and Methods Consecutive BRAF-tested Australian patients with metastatic melanoma (n = 197) were observed prospectively. A comprehensive range of clinicopathologic variables were correlated with BRAF mutation status, and a survival analysis was conducted. Results Forty-eight percent of patients had a BRAF mutation; 70 patients (74%) had V600E, 19 (20%) had V600K, and six (6%) had other genotypes. Other than age at diagnosis of distant metastasis (median age, 56 v 63 years for BRAF-mutant v BRAF wild-type patients, respectively; P < .001), there was no significant difference in clinical features of patients with metastatic melanoma by mutation status. Features of the antecedent primary melanoma significantly associated with a BRAF mutation (P < .05) were histopathologic subtype, presence of mitoses, single or occult primary melanoma, truncal location, and age at diagnosis of primary tumor ≤ 50 years. The interval from diagnosis of first-ever melanoma to distant metastasis was not significantly different between BRAF-mutant and BRAF wild-type patients; however, the median survival of patients with newly diagnosed metastatic melanoma was 5.7 months for BRAF-mutant patients not treated with a BRAF inhibitor, 8.5 months for BRAF wild-type patients, and not reached for BRAF-mutant patients treated with a BRAF inhibitor. Conclusion V600K mutations comprised 20% of BRAF mutations. Characteristics of the antecedent primary melanoma and age at diagnosis differed in BRAF-mutant and BRAF wild-type patients. The presence of mutant BRAF had no impact on the disease-free interval from diagnosis of first-ever melanoma to first distant metastasis; however, it may have impacted survival thereafter.

New Treatments for Cutaneous Metastatic Melanoma: MAPK Pathway-Targeted and Immune Based Therapies

2015 ◽  
Vol 15 (4) ◽  
pp. 461-467 ◽  
Author(s):  
F. Ranchon ◽  
A. Boespflug ◽  
C. Rioufol ◽  
V. Schwiertz ◽  
L. Thomas ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Mapk Pathway ◽  
New Treatments

scholarly journals Evaluation of Merkel Cell Polyomavirus DNA in Tissue Samples from Italian Patients with Diagnosis of MCC

Viruses ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 61
Author(s):  
Carla Prezioso ◽  
Raffaella Carletti ◽  
Francisco Obregon ◽  
Francesca Piacentini ◽  
Anna Maria Manicone ◽  
...  
Keyword(s):  
Point Mutations ◽  
Merkel Cell Polyomavirus ◽  
Merkel Cell ◽  
Tissue Samples ◽  
Metastatic Lesions ◽  
Formalin Fixed Paraffin ◽  
Formalin Fixed Paraffin Embedded ◽  
Metastatic Sites ◽  
Archived Specimens ◽  
Coding Control

Because the incidence of Merkel cell carcinoma (MCC) has increased significantly during the last 10 years and it is recognized that Merkel cell polyomavirus (MCPyV) and ultraviolet (UV) radiation represent two different etiological inputs sharing clinical, histopathological, and prognostic similar features, although with different prognosis, this study investigated the detection of MCPyV in skin and lymph nodes with histological diagnosis of MCC. Formalin-fixed paraffin-embedded tissue (FFPE) were retrieved from archived specimens and MCPyV non-coding control region (NCCR) and viral capsid protein 1 (VP1) sequences were amplified and sequenced. Results provide an interesting observation concerning the discrepancy between the MCPyV DNA status in primary and metastatic sites: in fact, in all cases in which primary and metastatic lesions were investigated, MCPyV DNA was detected only in the primary lesions. Our data further support the “hit-and-run” theory, also proposed by other authors, and may lead to speculation that in some MCCs the virus is only necessary for the process of tumor initiation and that further mutations may render the tumor independent from the virus. Few point mutations were detected in the NCCR and only silent mutations were observed in the VP1 sequence compared to the MCPyV MCC350 isolate. To unequivocally establish a role of MCPyV in malignancies, additional well-controlled investigations are required, and larger cohorts should be examined.

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