BRAF Mutations Research Articles

Cooperative genomic lesions in HRAS-mutant cancers predict resistance to farnesyltransferase inhibitors.

In the clinical development of farnesyltransferase inhibitors (FTIs) for HRAS-mutant tumors, responses varied by cancer type. Co-occurring mutations may affect responses. We aimed to uncover cooperative genetic events specific to HRAS-mutant tumors and to study their effect on sensitivity to FTIs. Using targeted sequencing data from the MSK-IMPACT and Dana-Farber Cancer Institute Genomic Evidence Neoplasia Information Exchange databases, we identified comutations that were observed predominantly in HRAS-mutant versus KRAS-mutant or NRAS-mutant cancers. HRAS-mutant cancers had a higher frequency of coaltered mutations (48.8%) in the MAPK, PI3K, or RTK pathway genes, compared with KRAS-mutant (41.4%) and NRAS-mutant (38.4%) cancers (p < 0.05). Class 3 BRAF, NF1, PTEN, and PIK3CA mutations were more prevalent in HRAS-mutant lineages. To study the effects of comutations on sensitivity to FTIs, HrasG13R was transfected into "RASless" (Kraslox/lox/Hras-/-/Nras-/-/RERTert/ert) mouse embryonic fibroblasts (MEFs), which sensitized nontransfected MEFs to tipifarnib. Comutation in the form of Pten or Nf1 deletion and Pik3caH1047R transduction led to resistance to tipifarnib in HrasG13R-transfected MEFs in the presence or absence of KrasWT, whereas BrafG466E transduction led to resistance to tipifarnib only in the presence of KrasWT. Combined treatment with tipifarnib and MEK inhibition sensitized cells to tipifarnib in all settings, including in MEFs with PI3K pathway comutations. HRAS-mutant tumors demonstrate lineage-dependent MAPK or PI3K pathway alterations, which confer resistance to tipifarnib. The combined use of FTIs and MEK inhibition is a promising strategy for HRAS-mutant tumors.

Investigating EGFR, BRAF, and RAS Mutations in Oral and Cutaneous Squamous Cell Neoplasms: A Preliminary Report on Romanian Patients

Background: Head and neck cancers, and particularly, oral cancers have a complex pathogenesis that includes genetic mutations and epigenetic alterations which interfere with cellular signaling and can trigger tumor development. The purpose of this study was to reveal whether low-frequency hotspot mutations may be detected in a study lot with histopathological evidence of squamous cell carcinoma (SCC) of the oral mucosa and skin of the head and neck. Methods: Tumor biopsies from treatment naïve patients were tested for BRAF V600, NRAS G12/G13, NRAS Q61, KRAS Q61 mutations, and EGFR exon 19 deletions (Ex19Del) using droplet digital PCR (ddPCR). The tumors were also analyzed for EGFR T790M mutations by RT-PCR, using a CE-IVD validated kit, with a limit of detection of 0.05%. Results: None of the examined cases exhibited NRAS G12/G13, NRAS Q61, KRAS Q61, BRAF V600, or EGFR T790M mutations, indicating that these alterations are rare events in SCC pathogenesis. Interestingly, among the 12 specimens tested by ddPCR for EGFR Ex19Del, an HPV-negative cSCC tumor occurring in the parotid region tested positive for this drug-sensitizing mutation, offering unexplored therapeutic perspectives to the patient from whom it was collected. Conclusions: Our study highlights the important clinical implications of detecting low-frequency hotspot mutations in tumor biopsies by ddPCR. We believe that the ddPCR-assisted analysis of these mutations in larger SCC cohorts may provide us with mechanistic insights regarding their role in SCC pathogenesis and guide the development of novel therapeutic strategies for this problematic disease.

Unveiling the role of KRAS in Chinese colorectal cancer patients: a positive influence on tumor mutational burden.

One of the main challenges associated with the development of therapeutic and diagnostic strategies for patients with colorectal cancer (CRC) is the establishment of minimally invasive and efficient biomarkers. Pertinent genes in CRC have been identified through their functions in systematic mutagenesis screens. KRAS is considered a dominant mutated oncogene that contributes to pathogenesis of CRC. This study aimed to explore the genomic alternations of KRAS in a CRC population. Sequencing data of 94 Chinese patients with CRC were prospectively collected and analyzed using next-generation sequencing (NGS). The influence of KRAS and its associated subtype co-mutations on the expression level of the tumor mutational burden (TMB) was investigated. The objective of our study was to assess the potential prognostic significance of KRAS and other driving oncogenes in determining the clinical efficacy of immunotherapy. The gene mutation rates of TP53, APC, and KRAS were 81.91%, 71.28%, and 43.62%, respectively. Additionally, KRAS G12D displayed a relatively higher mutation rate than other KRAS-mutant subtypes. Increased TMB was observed in cases of KRAS and BRAF mutation combined with APC single mutation; furthermore, the expression of TMB in G12V was the highest, and G12D presented the lowest TMB in single KRAS-mutant subtypes or the combination with APC mutations. The TMB driven by KRAS co-mutations may have the potential to be used as a key biomarker for prediction of treatment outcomes of immune checkpoint inhibitors (ICIs) in patients with CRC, especially with APC co-mutation.

612O Preliminary results from a phase I study of CFT1946, a novel BIDAC degrader in mutant BRAF V600 solid tumors

612O Preliminary results from a phase I study of CFT1946, a novel BIDAC degrader in mutant BRAF V600 solid tumors

A Case Report of Unrespectable Liver Metastases from Cancer Rectosigmoid Colon with Survival Greater Than 6 Years and Clinical Benefit after Multidisciplinary Treatment

Introduction Colorectal cancer represents 1,271 new cases per year in Morocco, However, over the last 30 years we have witnessed a significant increase in the overall survival of metastatic patients due to the arrival of new molecules.  Case Presentation We report the case of a 51 years old african female patient diagnosed for a moderately differentiated adenocarcinoma of the rectosigmoid junction MSS, wild RAS/BRAF, treated with colorectal protection and lymph node dissection, followed by 6 cycles of fulfol- cisplatin as an adjuvant. the follow up revealed the appearance of hepatic masses. The liver biopsy was performed showing a secondary localization of an adenocarcinoma of digestive origin. The patient received four lines of the chemotherapy, anti-EGFR antibodies and immunotherapy following the guidelines. However, since no KRAS NRAS BRAF mutation was detected at the DNA level circulating tumor, no rechallenging of the anti- EGFR was possible. The hepatic progression continued with appearance of pulmonary lesions, the decision was made for a palliative care.  Conclusion Our case highlights that due to the emergence of new effective molecules currently available, associated with a dedicated onco-surgical approach, more patients will be able to benefit from prolonged survival that did not seem achievable at the time of diagnosis.

Diagnostic Value of Conventional Polymerase Chain Reaction for Detecting BRAF V595E Mutation in Liquid and Tissue Specimens of Canine Urothelial and Prostate Carcinomas.

Canine urothelial carcinoma (UC) and prostatic carcinoma (PC) often present diagnostic challenges due to their anatomical locations. The BRAF V595E mutation, analogous to the human BRAF V600E mutation, has been identified in UC and PC. Digital PCR of urine is a non-invasive diagnostic method of mutation detection, but the availability of the necessary equipment is limited. This study aimed to develop a conventional PCR to detect the BRAF V595E mutation in urine and prostatic wash specimens from dogs with UC or PC. Specific primers for detecting wild-type and mutant BRAF V595E genes were validated in 34 formalin-fixed paraffin-embedded (FFPE) tissues, 116 urine samples, and 9 prostatic wash specimens. The results showed that the BRAF V595E mutation detection rate for UC and PC in the tissues was 51.6%. The detection rate in liquid specimens from dogs with lower urinary tract or prostate masses was 53.2%. Of the 41 cases with follow-up, 16 were further diagnosed with UC or PC, with 75% of liquid specimens from these dogs showing the BRAF V595E mutation. This conventional PCR method provides a reliable and non-invasive screening tool for UC and PC in dogs, especially in settings without advanced equipment.

Real-world evidence on efficacy and toxicity of targeted therapy in older melanoma patients treated in a tertiary-hospital setting.

Melanoma is the deadliest form of skin cancer. The median age at diagnosis is 66. While most patients are treated with immunotherapy, the use of targeted therapy is a valid alternative for patients whose tumors harbor a BRAF or c-KIT driver mutation. These agents, while effective, come with a variety of side effects which limit their use, especially in older patients. We sought to assess the efficacy and toxicity of these agents in older melanoma patients. Melanoma patients over 65 treated with BRAF/MEK or c-KIT inhibitors were retrospectively identified, and their data were analyzed for treatment efficacy and toxicity. All data were compared using the Chi-square test for categorical comparisons and the Kruskal-Wallis method for median comparisons. One hundred and sixteen patients were identified. One hundred and six patients were treated with BRAF/MEK inhibitors. The assessed response rate (RR) was 83% and was comparable across different subgroups, including advanced line patients and those with a more aggressive disease. The median progression free survival (PFS) was 7.9 months, and the median overall survival (OS) was 15.7 months. Twenty-seven percent experienced grade 3-4 toxicity leading to a 24% treatment discontinuation rate. Another 10 patients were treated with the c-KIT inhibitor imatinib, for whom the assessed RR was 55%. The median PFS was 4.3 months, and the median OS was 22.6 months. Forty percent needed dose reductions, yet none had to stop treatment due to adverse effects. The use of targeted therapy in older patients is effective yet challenging due to toxicity. Deploying mitigation strategies can help maximizing their usefulness.

An observational study on the efficacy of targeted therapy for pulmonary sarcomatoid carcinoma

BackgroundPulmonary sarcomatoid carcinoma is a rare tumor that is resistant to cytotoxic agents. This observational study aimed to evaluate the detection rate of driver gene alteration and the efficacy of targeted therapy for pulmonary sarcomatoid carcinoma.MethodsWe established a database of patients with pulmonary sarcomatoid carcinoma and their clinical information, including EGFR mutation, ALK fusion gene, ROS1 fusion gene, BRAF mutation, and MET exon 14 skipping mutation. The present study retrieved and analyzed the data of patients with pulmonary sarcomatoid carcinoma in whom driver gene alterations were evaluated, and the survival duration after the initiation of treatment with targeted therapy was examined.ResultsA total of 44 patients were included in the present study. The EGFR mutation, ALK fusion gene, and MET exon 14 skipping mutation were detected in 2/43 patients (4.7%), 2/34 patients (5.9%), and 2/16 patients (12.5%), respectively. The ROS1 fusion gene (0/18 patients) and BRAF mutation (0/15 patients) were not detected. Female patients (P = 0.063, Fisher’s exact test) and patients without smoking history (P = 0.025, Fisher’s exact test) were the dominant groups in which any driver mutation was detected. Five patients with driver gene alterations were treated with targeted therapy. Progression-free survival (PFS) was 1.3 months and 1.6 months in 2 of the patients treated with gefitinib. Two patients with the ALK fusion gene showed 2.1 and 14.0 months of PFS from the initiation of treatment with crizotinib, and a patient with the MET exon 14 skipping mutation showed 9.7 months of PFS from the initiation of treatment with tepotinib.ConclusionThe EGFR mutation, ALK fusion gene, and MET exon 14 skipping mutation were detected in patients with pulmonary sarcomatoid carcinoma in clinical practice, and some patients achieved long survival times after receiving targeted therapy. Further investigation is necessary to evaluate the efficacy of targeted therapy for pulmonary sarcomatoid carcinoma.

PIK3CA Mutated Colorectal Cancers Without KRAS, NRAS and BRAF Mutations Possess Common and Potentially Targetable Mutations in Epigenetic Modifiers and DNA Damage Response Genes.

Despite therapeutic advancements, metastatic colorectal cancer is usually fatal, necessitating novel approaches based on the molecular pathogenesis to improve outcomes. Some colorectal cancers have no mutations in the extended RAS panel (KRAS, NRAS, BRAF) genes and represent a special subset, which deserves particular therapeutic considerations. The genomic landscape of colorectal cancers from publicly available genomic series was interrogated, using the cBioportal platform. Colorectal cancer cohorts with cancers devoid of KRAS/NRAS or BRAF mutations were evaluated for the presence of mutations in the catalytic sub-unit alpha of kinase PI3K, encoded by the gene PIK3CA. PIK3CA mutations in the absence of KRAS/NRAS/BRAF mutations were observed in 3.7% to 7.6% of colorectal cancers in the different series examined. Patients with all four genes in wildtype configuration (quadruple wild type) represented 32.2% to 39.9% of cases in the different series examined. Compared with quadruple wild type cancers, triple (KRAS/NRAS/BRAF) wild type/PIK3CA mutated cancers had a higher prevalence of high TMB cases and additional mutations in colorectal cancer associated genes except for mutations in TP53. Mutations in genes encoding for epigenetic modifiers and the DNA damage response (DDR) were also more frequent in triple wild type/PIK3CA mutated cancers. The prognosis of the two groups was comparable. Colorectal cancers with PIK3CA mutations in the absence of KRAS/NRAS/BRAF mutations have frequently mutations in epigenetic modifiers and DDR response genes, which may provide opportunities for targeting. These mutations are present in a smaller subset of quadruple wild type cancers.

Development of a Novel System Consisting of a Reductase-Like Nanozyme and the Reaction of Resazurin and Ammonia Borane for Sensitive Fluorometric Sensing.

We report a novel system consisting of a redox reaction and a highly efficient reductase-like nanozyme, silica-palladium nanoparticles (Pd@SiO2 NPs), as a novel detection platform for fluorometric sensing. In a proof-of-concept demonstration using an oligonucleotide as the detection target, a glass fiber-based sensor is fabricated by covalently conjugating two oligo probes, which are complementary to the adjacent segments of the target oligonucleotide, on Pd@SiO2 NPs and glass fiber, respectively. In the presence of the target oligonucleotide, the two probes are drawn together by the target through sequence-specific hybridization, bringing the Pd@SiO2 NPs to the glass fiber. When the glass fiber is subsequently immersed in a mixture of resazurin and ammonia borane solution, the Pd@SiO2 NPs on the glass fiber trigger the catalytic conversion of resazurin (blue, slightly fluorescent) to resorufin (pink, highly fluorescent) with massive signal amplification, indirectly signaling the presence of the target oligonucleotide. We show that the glass fiber-based fluorometric sensor can detect a target oligonucleotide associated with the BRAF mutation linearly in the concentration range of 20 to 400 pM with a detection limit (LOD) of 15 pM and the specificity to differentiate targets with single-base difference. These results demonstrate a new frontier for the development of a sensitive, specific, and inexpensive nonenzyme-based fluorometric sensing platform as an alternative to conventional enzyme-based assays.

Clinicopathological features, response patterns, outcomes and BRAF status in patients with advanced acral melanoma: a preliminary Peruvian study.

Globally, acral melanoma (AM) is underrepresented in most clinical trials, being predominant in Caucasian populations. Latin America is a niche that needs to be explored. Therefore, this study aimed to determine the clinical features, response patterns, outcomes and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) status in Peruvian patients with advanced AM. We retrospectively reviewed the medical records of 19 patients with advanced AM who received immunotherapy (IO) in first- or subsequent-line therapy. The samples were analysed, and their mutational state was performed by deoxyribonucleic acid sequencing, focusing primarily on the most frequently mutated gene, BRAF. Descriptive statistics were used to assess the baseline characteristics. Overall survival was estimated using the Kaplan-Meier method. The median age was 64 years and 63.2% were men. Plantar was the site most frequently affected (84.2%). The most frequent stage was stage III (68.4%), with 26.4% receiving adjuvant therapy. The majority of cases exhibited a Breslow thickness of >4 mm (52%), a Clark level of IV/V (89.4%), and all patients presented ulceration and a high range of mitosis. During follow-up, all patients experienced recurrent advanced disease, with 52.6% developing visceral metastasis. Patients who received IO as first or subsequent line had an overall response rate (ORR) of 33.3%, and those who received it as first-line therapy had an ORR of 40%. Twenty-one percent of the patients harbored BRAF V6000E mutation and, showing an ORR of 50% compared to wild-type individuals (44.4%) after the first line of treatment. Our preliminary study reported that AM has poor clinico-pathological features and response rates to IO in Peruvian patients. However, those who received IO as a first-line treatment or harbored the BRAF mutation appeared to have a slightly better response than wild-type patients.

BRAF mutation is associated with tumor volume doubling time of thyroid microcarcinoma during active surveillance

BRAF mutation is associated with tumor volume doubling time of thyroid microcarcinoma during active surveillance

Multi-omics analysis delineates resistance mechanisms associated with BRAF inhibition in melanoma cells

Mutant BRAF is a critical oncogenic driver in melanoma, making it an attractive therapeutic target. However, the success of targeted therapy using BRAF inhibitors vemurafenib and dabrafenib has been limited due to development of resistance, restricting their clinical efficacy. A prior knowledge of resistance mechanisms to BRAFi or any cancer drug can lead to development of drugs that overcome resistance thus improving clinical outcomes. In vitro cellular models are powerful systems that can be utilized to mimic and study resistance mechanisms. In this study, we employed a multi-omics approach to characterize a panel of BRAF mutant melanoma cell lines to develop and systematically characterize BRAFi persister and resistant cells using exome sequencing, proteomics and phosphoproteomics. Our datasets revealed frequently observed intrinsic and acquired, genetic and non-genetic mechanisms of BRAFi resistance that have been studied in patients who developed resistance. In addition, we identified proteins that can be potentially targeted to overcome BRAFi resistance. Overall, we demonstrate that in vitro systems can be utilized not only to predict resistance mechanisms but also to identify putative therapeutic targets.

Targeting Non-V600 Mutations in BRAF: A Single Institution Retrospective Analysis and Review of the Literature.

While successful treatment paradigms for BRAF V600 mutations have been developed, 10% of BRAF mutations are not at V600 and lack a standard treatment regimen. This study summarizes the current body of knowledge on the treatment of non-V600 mutations and reports a single institution experience. We conducted a literature review to summarize relevant preclinical and clinical published data on the response of non-V600 mutations to targeted therapies. We performed a retrospective analysis of INOVA Schar Cancer patients registered in our Molecular Tumor Board database with non-V600 BRAF mutations who were recipients of targeted therapy and assessed their time to next treatment and best response. Published preclinical and clinical data have demonstrated limiting results in the response of non-V600 mutated cancers to targeted therapies. Response rates were variable for the major classes of BRAF mutations including class II and class III mutations as well as, BRAF fusions. Data collected from our INOVA cohort offered promising results with one patient achieving partial remission and two patients achieving stable disease. This article reflects the current understanding of targeted therapies in non-V600 mutations. Further large-scale studies separating BRAF mutations based on their mechanism of activation will expand our understanding.

First line therapy in stage IV BRAF mutated colorectal cancer

IntroductionThe molecular profile of colorectal cancer (CRC) plays a crucial role in understanding patient prognosis and treatment response. Within CRC, a distinct subgroup can be identified by the presence of the BRAF V600E mutation. This specific mutation, classified as Class I of BRAF mutations, is known to be associated with a poor prognosis and resistance to standard therapy. To determine the most effective treatment approach for this specific subgroup of CRC, we conducted a network meta-analysis (NMA) to compare various pharmacological interventions and evaluate their relative effectiveness in BRAF-mutated CRCs. Materials and methodsOn July 31, 2023, we conducted a systematic search of PubMed, Cochrane Central Register of Controlled Trials, and Embase. The inclusion criteria were as follows: 1) reporting of outcomes in patients with BRAF-mutated CRC who underwent first-line chemotherapy; 2) reporting of survival information as hazard ratios (HR); and 3) publication in English. The data were combined using HRs for overall and progression-free survival (OS and PFS) using random-effects models. NMA was performed under the Bayesian framework, utilizing the GeMTC package. The relative rankings of the treatments were determined using SUCRA scores. ResultsA total of 16 studies were included. When compared to standard chemotherapy (CT) doublets (such as FOLFOX or FOLFIRI), none of the comparison arms demonstrated a gain in OS. CT doublet + bevacizumab did not show significant superiority over either CT doublet alone or 5FU/capecitabine + bevacizumab. FOLFOXIRI and FOLFOXIRI + bevacizumab did not show superiority over any other treatment schedule that was compared. CT doublets + bevacizumab had the highest SUCRA score (0.87), followed by single-agent fluoropyrimidines + bevacizumab (0.61), and FOLFOXIRI (0.56). Regarding PFS, no regimen was found to be superior to the combination of CT doublet plus bevacizumab. However, FOLFOXIRI + bevacizumab + atezolizumab showed a tendency towards better results (HR = 0.26, 95 % CI 0.05–1.1). ConclusionsOur review suggests that a CT doublet with bevacizumab is the most favorable option for OS. However, a reasonable alternative could be a triplet CT without bevacizumab.

Effect of TTF-1 expression on progression free survival of immunotherapy and chemo-/immunotherapy in patients with non-small cell lung cancer

BackgroundThe choice between immunotherapy with a checkpoint inhibitor (CPI) and chemo-/immunotherapy (CIT) in patients with NSCLC stage IV is often discussed. There is some data that the effect of chemotherapy is influenced by TTF-1 expression. Little is known about the influence of thyreoid transcription factor 1 (TTF-1) expression on CIT and CPI therapy. We aimed to investigate the relationship between tumor TTF-1 expression and efficacy of CIT and CPI therapy.Patients and methodsWe retrospectively analysed 130 patients (age 68 ± 7 y) with NSCLC stage IV. Only patients with lung adenocarcinoma were included. Patients with ALK, ROS1, RET, MET, NTRK, EGFR, BRAF mutation were excluded. Patients were treated according to the guidelines with either CPI alone (pembrolizumab, nivolumab, atezolizumab, cemiplimab) or CIT (Carboplatin/Pemetrexed/Pembrolizumab, Carboplatin/Paclitaxel/Atezolizumab). We registered patients’ characteristics including TTF-1 expression. Group 1 consisted of 40 patients with CPI and TTF-1 expression, group 2 were 26 patients with CPI and with no TTF-1 expression. Group 3 consisted of 41 patients with CIT and TTF-1 expression, group 4 were 23 patients with CIT and with no TTF-1 expression.ResultsGroup 1–4 showed comparable patients characteristics. Using cox-regression analysis, we found that TTF-1 expression resulted in an improved progression free survival (PFS) compared to patients with CPI and no TTF-1 expression (18 ± 3,15 vs. 5 ± 0,85 months, p = 0.004, 95% CI: 0,23 − 0,984). In patients, who were treated with CIT, PFS was also increased in patients with TTF-1 expression (9 ± 3,17 vs. 3 ± 0,399 months, p = 0.001, 95% CI: 0,23 − 0,85).ConclusionsIn a real-life setting, we found that TTF-1 expression is associated with an increased PFS. Patients with chemo-/immunotherapy and immunotherapy seem to have a better therapy response in pulmonary adenocarcinoma with TTF-1 expression.

Computational Modeling of Drug Response Identifies Mutant-Specific Constraints for Dosing panRAF and MEK Inhibitors in Melanoma.

This study explores the potential of pre-clinical in vitro cell line response data and computational modeling in identifying the optimal dosage requirements of pan-RAF (Belvarafenib) and MEK (Cobimetinib) inhibitors in melanoma treatment. Our research is motivated by the critical role of drug combinations in enhancing anti-cancer responses and the need to close the knowledge gap around selecting effective dosing strategies to maximize their potential. In a drug combination screen of 43 melanoma cell lines, we identified specific dosage landscapes of panRAF and MEK inhibitors for NRAS vs. BRAF mutant melanomas. Both experienced benefits, but with a notably more synergistic and narrow dosage range for NRAS mutant melanoma (mean Bliss score of 0.27 in NRAS vs. 0.1 in BRAF mutants). Computational modeling and follow-up molecular experiments attributed the difference to a mechanism of adaptive resistance by negative feedback. We validated the in vivo translatability of in vitro dose-response maps by predicting tumor growth in xenografts with high accuracy in capturing cytostatic and cytotoxic responses. We analyzed the pharmacokinetic and tumor growth data from Phase 1 clinical trials of Belvarafenib with Cobimetinib to show that the synergy requirement imposes stricter precision dose constraints in NRAS mutant melanoma patients. Leveraging pre-clinical data and computational modeling, our approach proposes dosage strategies that can optimize synergy in drug combinations, while also bringing forth the real-world challenges of staying within a precise dose range. Overall, this work presents a framework to aid dose selection in drug combinations.

Non-coding RNAs in BRAF-mutant melanoma: targets, indicators, and therapeutic potential.

Melanoma, a highly aggressive skin cancer, is often driven by BRAF mutations, such as the V600E mutation, which promotes cancer growth through the MAPK pathway and contributes to treatment resistance. Understanding the role of non-coding RNAs (ncRNAs) in these processes is crucial for developing new therapeutic strategies. This review aims to elucidate the relationship between ncRNAs and BRAF mutations in melanoma, focusing on their regulatory roles and impact on treatment resistance. We comprehensively reviewed current literature to synthesize evidence on ncRNA-mediated regulation of BRAF-mutant melanoma and their influence on therapeutic responses. Key ncRNAs, including microRNAs and long ncRNAs, were identified as significant regulators of melanoma development and therapy resistance. MicroRNAs such as miR-15/16 and miR-200 families modulate critical pathways like Wnt signaling and melanogenesis. Long ncRNAs like ANRIL and SAMMSON play roles in cell growth, invasion, and drug susceptibility. Specific ncRNAs, such as BANCR and RMEL3, intersect with the MAPK pathway, highlighting their potential as therapeutic targets or biomarkers in BRAF-mutant melanoma. Additionally, ncRNAs involved in drug resistance, such as miR-579-3p and miR-1246, target processes like autophagy and immune checkpoint regulation. This review highlights the pivotal roles of ncRNAs in regulating BRAF-mutant melanoma and their contribution to drug resistance. These findings underscore the potential of ncRNAs as biomarkers and therapeutic targets, paving the way for innovative treatments to improve outcomes for melanoma patients.

Frequency of BRAF Mutations in Dysplastic Nevi, Lentigo Maligna, and Melanoma In Situ.

Background: In melanomas, mutations in the BRAF gene are common and their occurrence represents an early oncogenic event. Our goal was to determine and compare the frequency of BRAF gene mutations in dysplastic nevi (ND) and melanomas in situ (MIS), as well as whether there is a correlation between the presence of BRAF gene mutations and various anamnestic, clinical, and histopathologic variables. Methods: A total of 175 patients-106 with ND, 41 with MIS, and 28 with lentigo maligna (LM) were included in the study. DNA was extracted from tissue samples and analyzed using the competitive allele-specific TaqMan chain reaction by polymerase in real time to detect the presence of BRAF V600E and V600K mutations. The data were compared with anamnestic, clinical, and histopathological data. Results: There is a statistically significant correlation between the presence of BRAF mutation and the diagnosis of melanoma in situ (χ2 test, χ2 = 29.17, p < 0.0001). Patients with LM had a significantly lower incidence of BRAF mutations compared to patients with ND and MIS. There was a significant correlation between the presence of a BRAF mutation and tumor localization, as well as the age of the patient, but no statistically significant correlation between the presence of a BRAF mutation and sex, tumor size, or previous melanoma diagnosis. Conclusions: BRAF mutations in ND are essentially required; however, they are an insufficient oncogenic trigger for the development of melanoma. This research contributes to a better understanding of the etiopathogenesis of melanoma and the role of ND as possible precursor lesions.

Anaplastic thyroid cancer: A review of recent evidence and summary of an Australian institutional protocol.

Anaplastic thyroid cancer (ATC), a rare and highly aggressive malignancy, is characterized by an exceptionally poor prognosis, where the majority of patients present with extensive local invasion and/or distant metastases. 20-30% of ATCs harbor the BRAF-V600E mutation. Neoadjuvant BRAF-targeted therapy may have the potential to downstage and facilitate surgical resection for patients with locally advanced and unresectable primary tumors with BRAF mutation and may convey a survival advantage in those with metastatic disease. There is emerging evidence to support the use of other targeted agents, including multikinase inhibitors, as well as the incorporation of immunotherapy into the treatment regimen. Rapid molecular and pathological diagnosis and expert multidisciplinary discussion at specialized treatment centers are critical to expedite investigations and initiate treatment for this complex and rapidly progressive disease.