BRAF Mutations Research Articles

Exploring Marine Compounds for Inhibition of the BRAF V600E Mutation in Lung Cancer: A High Throughput Virtual Screening Approach

The BRAF V600E mutation is present in a variety of cancer cell types, including lung cancer, which is a leading cause of cancer-related death globally. Drugs like Dabrafenib and Vermaifenib were specifically used in targeted therapy for patients with BRAF V600E mutation. Drug resistance is typical, though, and more study is required to improve therapeutic strategies for this subset of lung cancer. Recently, marine natural compounds have emerged as a resource for the development of novel cancer therapeutics. In this study, we used virtual screening of marine compounds to find potential therapeutic candidates for NSCLC patients with the BRAF V600E mutation. We developed a receptor-based pharmacophore model and screened a library of 31,561 compounds from the Comprehensive Marine Natural Products Database (CMNPD) using a virtual screening protocol that was constructed and validated. Molecular docking was performed using CDOCKER to investigate potential inhibitors and ADMET for their toxicity and other properties. Seven compounds exhibited higher efficacy than the experimentally verified compound of BRAF mutation. A molecular dynamics simulation was performed to confirm the stability of the docked compounds and compare them with the experimentally verified compound. Our study identified, out of seven, the CMNPD7700 compound as a potential drug candidate for further development due to its high, effectiveness and molecular stability.

Distinct Transcriptomic and Tumor Microenvironment Profiles in Sinonasal Mucosal Melanoma and Aggressive Cutaneous Melanomas.

Background/Objectives: Sinonasal mucosal melanoma (SNMM) is a rare and aggressive melanoma subtype with a notably poor prognosis compared to cutaneous melanoma (CM). Despite advances in molecular characterization, SNMM remains underexplored, posing a clinical challenge and highlighting the need for detailed molecular profiling. This study aimed to identify the molecular features of SNMM, elucidate its clinical behavior and prognostic implications, and provide insights for improved therapeutic strategies. Methods: This retrospective study analyzed 37 primary melanoma tumors diagnosed at the Hospital Clinic of Barcelona. Gene expression was examined using 1402 immuno-oncology-related probes through next-generation sequencing. Hierarchical clustering analysis (HCA), differentially expressed genes (DEGs), gene set enrichment analysis (GSEA), and the xCell algorithm were performed. The statistical methods comprised descriptive statistics, clinical variable associations, and survival analyses. Results: HCA revealed two primary clusters. Cluster A exclusively contained CM tumors (20/24), while cluster B included all SNMMs (13/13) and some CMs (4/24). Cluster B showed a higher average age at diagnosis (p = 0.018), higher mitotic index (p = 0.0478), fewer BRAF mutations (p = 0.0017), and poorer melanoma-specific survival (p = 0.0029). Cluster B showed 602 DEGs with cell cycle pathways enriched, immune pathways diminished, lower immune scores (p < 0.0001), and higher stromal scores (p = 0.0074). Conclusions: This study revealed distinct molecular characteristics and an altered tumor microenvironment in SNMMs and certain aggressive CMs. Identifying specific genes and pathways involved in cell cycle progression and immune evasion suggests potential prognostic markers, offering new avenues for enhancing treatment strategies and improving patient survival rates.

Real-World Data of Patients with BRAF V600E-Mutated Metastatic Colorectal Cancer Treated with Trifluridine/Tipiracil.

For patients with refractory metastatic colorectal cancer (mCRC), trifluridine/tipiracil (FTD-TPI) has been associated with a significant improvement in overall survival (OS). However, data are lacking regarding the activity of FTD-TPI in patients with BRAF-mutated mCRC. This retrospective, multicenter, international cohort included patients with BRAF-mutated mCRC treated with FTD-TPI in a real-life setting in Spain and Italy. Survival analysis was performed using Kaplan-Meier methods and Cox proportional hazard models and according to established prognostic groups: good prognosis characteristics (GPC; < 3 metastatic sites and time from metastases to FTD-TPI ≥ 18 months) and poor prognosis characteristics (PPC; ≥ 3 metastatic sites or time from metastases to FTD-TPI < 18 months). In the 26 patients included, the median age was 61 years, 13 (50%) were female, and 20 (77%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 1. Fourteen (56%) patients had right-sided tumors, six (23%) had microsatellite instability tumors, and thirteen (50%) had liver metastases. Median progression-free survival was 2.3 months (95% CI 2.0-3.2), and median OS (mOS) was 6.6 months (95% CI 4.4-12.0). mOS was 7.6 vs. 4.2 months (HR 1.64, 95% CI 0.65-4.10, p = 0.3) for GPC and PPC patients, respectively. Exploratory analyses identified ECOG as the only feature associated with survival. The most frequent grade 3-4 adverse events were neutropenia (8%), anemia (8%), and asthenia (4%). Patients with BRAF mutant mCRC achieved modest benefits with FTD-TPI; however, patients with GPC and ECOG 0 achieved longer OS compared with those with PPC or ECOG 1-2, thus warranting further exploration in prospective cohorts.

CTHRC1 is associated with BRAF(V600E) mutation and correlates with prognosis, immune cell infiltration, and drug resistance in colon cancer, thyroid cancer, and melanoma.

Colon cancer, thyroid cancer, and melanoma are common malignant tumors that seriously threaten human health globally. The B-Raf proto-oncogene, serine/threonine kinase (BRAF)(V600E) mutation is an important driver gene mutation in these cancer types. In this study, we identified that collagen triple helix repeat containing 1 (CTHRC1) expression was associated with the BRAF(V600E) mutation in colon cancer, thyroid cancer, and melanoma. Based on database analysis and clinical tissue studies, CTHRC1 was verified to correlate with poor prognosis and worse clinicopathological features in colon cancer and thyroid cancer patients, but not in patients with melanoma. Several signaling pathways, immune cell infiltration, and immunotherapy markers were associated with CTHRC1 expression. Additionally, a high level of CTHRC1 was correlated with decreased sensitivity to antitumor drugs (vemurafenib, PLX-4720, dabrafenib, and SB-590885) targeting the BRAF(V600E) mutation. This study provides evidence of a significant correlation between CTHRC1 and the BRAF(V600E) mutation, suggesting its potential utility as a diagnostic and prognostic biomarker in human colon cancer, thyroid cancer, and melanoma.

Definitive Radiotherapy for Oligometastatic and Oligoprogressive Thyroid Cancer: A Potential Strategy for Systemic Therapy Deferral.

Definitive radiotherapy (dRT) has been shown to be an effective option for patients with oligometastatic and oligoprogressive cancers; however, this approach has not been well-studied in metastatic thyroid cancer. This retrospective cohort included 119 patients with oligometastatic (34%) and oligoprogressive (66%) metastatic thyroid cancer treated from 2005 to 2024 with 207 dRT courses for 344 sites (50% thoracic, 37% bone, 7.5% brain, 4% abdominopelvic, and 1.5% neck/skull base). Histologies included 61% papillary, 15% poorly differentiated, 13% follicular, and 10% oncocytic, and 114 (96%) patients had radioiodine-refractory disease prior to dRT. Each course involved 1 to 5 sites, with prescriptions intended for definitive control (median BED10, 72 Gy), and palliative RT was excluded. Somatic mutation testing for oncologic drivers was performed in 103 (87%) patients. Each patient had an average of 3 sites (range, 1-23) treated over 2 courses (range, 1-9). Follow-up from first dRT was a median 2.5 years, with overall survival at 3 and 5 years of 81.5% and 70%, respectively. Actuarial local control per site was 91% at 3 years. Median progression-free survival (PFS) after first course was 17 months (95% CI, 10-24 months), with poorly differentiated histology associated with worse outcomes (hazard ratio [HR], 2.20; 95% CI, 1.24-3.90; P=.007), BRAF mutation with improved PFS (HR, 0.59; 95% CI, 0.37-0.95; P=.029), and no significant findings with respect to systemic therapy. At initial dRT, 92 (77%) patients were not on systemic therapy; and after first dRT, freedom from systemic therapy escalation was a median 4.1 years (95% CI, 1.7-6.5 years), with 2- and 5-year continued deferral rates of 73% and 46%, respectively. Grade 3 toxicities were noted for 1.5% of courses, with no grade 4-5 events observed. This study underscores the potential of dRT as a feasible strategy for deferring systemic therapy escalation in patients with oligometastatic and oligoprogressive metastatic thyroid cancer, demonstrating that sequential dRT courses impart excellent local control and are safe to deliver repeatedly for multiple distant sites. Further studies are warranted to validate these findings and elucidate the full benefit of dRT as part of a multidisciplinary approach for metastatic thyroid cancer.

Colorectal Cancer: A Brief and Simplified Analysis of a Complex Disease.

Background and Objectives: This study examined factors influencing the onset and progression of colorectal tumors, including patients' epidemiological data, tumor location (right-sided, left-sided, and rectal), histomorphology, perineural or intraneural invasion, lymph node status, immune reactions, mismatch repair (MMR) status, and commonly observed mutations. Our primary goal was to evaluate their predictive and prognostic value and interactions. Materials and Methods: We analyzed a retrospective cohort of 100 patients with colorectal adenocarcinoma diagnosed between 2020 and 2023, using formalin-fixed paraffin-embedded (FFPE) tumor blocks. The methods included routine H&E microscopy, immunohistochemistry, Next-Generation Sequencing (NGS), and subsequent statistical analysis. Results: The findings showed a median diagnosis age of 70 years, with no gender-specific tumor localization. Right-sided tumors were prevalent, especially among patients with a defective MMR (dMMR), which represented 89% of dMMR cases. MMR status significantly correlated with tumor localization. We observed significant relationships between tumor grade, lymphovascular invasion, and overall tumor stage. Higher tumor grades and stages correlated with increased lymphovascular invasion and lymph node involvement. Interestingly, tumor budding did not correlate with lymph node metastasis but was significantly associated with higher tumor grades. Most BRAF mutations were found in right-sided tumors, indicating a significant correlation with this localization. Conclusions: This study focuses on the diversity of colorectal cancer (CRC) by examining how genetic and histological characteristics vary based on tumor location or other tumor variables.

Role of Annexin 7 (ANXA7) as a Tumor Suppressor and a Regulator of Drug Resistance in Thyroid Cancer.

Thyroid cancer is the most common endocrine malignancy in the United States, with an overall favorable prognosis. However, some patients experience poor outcomes due to the development of resistance to conventional therapies. Genetic alterations, including mutations in BRAF, Met, and p53, play critical roles in thyroid cancer progression, with the BRAF V600E mutation detected in over 60% of cases. This study investigates the tumor-suppressive role of Annexin A7 (ANXA7) in thyroid cancer, focusing on its potential impact on tumor behavior and therapeutic response. Our analysis, which included RNA sequencing and protein profiling, revealed reduced ANXA7 expression in thyroid cancer cells, particularly in those harboring the BRAF V600E mutation. Upon treatment with inhibitors targeting BRAF and MEK, ANXA7 expression increased, leading to reduced phosphorylation of ERK and activation of apoptotic pathways. Additionally, we identified the cyclin-dependent kinase inhibitor p21 as a key player in modulating resistance to BRAF inhibitors. Combination therapies aimed at concurrently increasing p21 and ANXA7 levels resulted in a marked enhancement of apoptosis. These findings suggest a previously uncharacterized regulatory network involving the ANXA7/p21/BRAF/MAPK/p53 axis, which may contribute to drug resistance in thyroid cancer. This study provides new insights into overcoming resistance to BRAF and MAPK inhibitors, with implications for treating thyroid cancer and potentially other BRAF-mutant tumors. Future efforts will focus on high-throughput screening approaches to explore ANXA7-targeted therapeutic strategies for thyroid cancer.

Abstract IA020: Discovery of brain-penetrant inhibitors for the treatment of BRAF mutant tumors

Abstract Many tumors are driven by oncogenic kinases. While a majority of the most prevalent oncogenic kinases currently have existing targeted therapies available, most of the molecules were not designed to be CNS penetrant and are therefore unable to control CNS metastatic tumors. By employing principles for the design of CNS penetrant molecules, we discovered two brain-penetrant BRAF inhibitors, which both progressed into clinical trials. The first candidate, ARRY-461, was designed to inhibit class I mutant BRAF V600E tumors. The second candidate, ARRY-440, was designed to inhibit class I, II, III, and indel mutant BRAF tumors. Additionally, ARRY-440 was designed to overcome both the paradoxical activation of BRAF as well as inhibit mBRAF:wtCRAF heterodimers, two features that most 1st generation BRAF V600E inhibitors lack. Finally, we were pleased to see that ARRY-440 led to clinical responses in a variety of different BRAF V600E tumors, including in some tumors that harbored both a BRAF V600E mutation and an oncogenic NRAS mutation. Citation Format: Dean Kahn. Discovery of brain-penetrant inhibitors for the treatment of BRAF mutant tumors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA020.

BRAFV600E/pTERT double mutated papillary thyroid cancers exhibit immune gene suppression

IntroductionBRAFV600E mutation (BRAFmut) is common in papillary thyroid cancer (PTC), and most patients have an excellent outcome. However, a TERT-promoter mutation (pTERTmut) in the presence of BRAFmut (BRAFmutpTERTmut) has been demonstrated to confer a more aggressive behavior to PTC. Lymphocytic infiltration is often present in PTC. In this study, we sought to decipher the relationship between the BRAF and pTERT mutations and immune gene dysregulation in tumor samples from a cohort of 147 samples of PTC.MethodsThe abundance of 770 immune gene transcripts was determined by multiprex capture/detection and digital counting of mRNA transcripts using the NanoString nCounter® PanCancer Immune Profiling Panel.ResultsWe identified 40 immune transcripts differentially expressed in BRAFmutpTERTmutvs BRAFmutpTERT wildtype (pTERTwt) (P&amp;lt;0.05). Transcripts induced by BRAFmut alone were significantly repressed in BRAFmutpTERTmut samples, such as genes expressed by lymphoid cells, antigen-presenting cells, and cytotoxic cells, including chemokines, cytokines, checkpoint control proteins, interferon downstream markers, TNF superfamily proteins and BMP markers. A validation analysis using 444 samples from The Cancer Genome Atlas (TCGA) PTC dataset yielded similar results. Deconvolution analysis confirmed differences in the immune cell populations such as increased presence of M2 macrophages in the BRAFmutpTERTmut Mayo cohort and a lower abundance of M1 macrophages in the BRAFmutpTERTmut TCGA cohort compared to BRAFmutpTERTwt. Most of the immune gene pathways were enriched in the BRAFmutpTERTwt tumors in both Mayo and TCGA cohorts but not in BRAFmutpTERTmut. BRAFmutpTERTwt had higher stromal lymphocytes infiltration as compared to BRAFwtpTERTwt tumors, corroborating the transcriptomic findings.DiscussionTo our knowledge this is the first report of a potential link between TERT and the immune microenvironment, offering an explanation for the aggressive nature of BRAFmutpTERTmut PTC.

PIK3CA Mutations and Co-Mutations in Operated Non-Small Cell Lung Carcinoma.

Background: Understanding PIK3CA mutations and co-mutations in non-small cell lung carcinoma (NSCLC) is critical to developing personalized treatment strategies. Therefore, this study aims to investigate PIK3CA mutations and the accompanying somatic variations in NSCLC. Methods: This retrospective study included 98 patients over 18 years of age who were diagnosed with NSCLC, operated on, and referred to the Molecular Pathology Laboratory between January 2019 and June 2024 for next-generation sequencing panel tests and ALK-ROS1 FISH analysis. Results: All patients were found to carry PIK3CA mutations. Among the 98 NSCLC patients analyzed, 16 (16.33%) were female and 82 (83.67%) were male. The average age of the patients was 64.53 ± 9.63 years, with an age range of 38-84 years, and the majority were 50 years or older. Of the cases, 51 presented the adenocarcinoma subtype, while the remaining 47 showed the squamous cell carcinoma subtype. A smoking history was present in 77 (78.57%) patients, while 21 (21.43%) had no smoking history. The most frequently detected pathogenic or likely pathogenic PIK3CA variations were c.1633G>A p.E545K (32.65%), c.1624G>A p.E542K (11.22%), c.3140A>G p.H1047R (11.22%), c.3140A>T p.H1047L (5.10%), c.1357G>C p.E453Q (4.08%), and c.3143A>G p.H1048R (2.04%). The top 10 mutations that most commonly accompanied PIK3CA variations were KRAS, NF1, TP53, EGFR, PTEN, BRAF, KIT, CDKN2A, SMARCA4, and ATM mutations, respectively. Conclusions:PIK3CA variations, along with other gene variations, may influence cancer progression and thus may play a crucial role in the determination of targeted treatment strategies.

Neurologic adverse events associated with BRAF and MEK inhibitor therapy in patients with malignant melanoma: a disproportionality analysis using the Food and Drug Administration Adverse Event Reporting System.

BRAF and MEK inhibitor (BRAFi + MEKi) therapy has improved the treatment of solid tumors with BRAF mutation. However, their neurologic adverse events (nAEs) have been largely unexplored. This study aimed to provide clinicians with more updated knowledge on nAEs associated with BRAFi + MEKi therapy in patients with malignant melanoma compared with nonmelanoma cancers. The United States Food and Drug Administration Adverse Event Reporting System was queried from 2011 to 2022 to capture nAEs reported for the BRAFi + MEKi therapies, vemurafenib plus cobimetinib (V + C), dabrafenib plus trametinib (D + T), and encorafenib plus binimetinib (E + B). A disproportionality analysis was performed to calculate their reporting odds ratios (RORs) and 95% confidence intervals (CIs) using a control group of antineoplastic medications. There were 2881 BRAFi + MEKi therapy-associated nAE cases, the majority of which listed malignant melanoma as the reason for use (87.5, 66.7, and 62.0% for V + C, D + T, and E + B, respectively). Several novel associations were identified; including epidural lipomatosis (ROR: 320.07, 95% CI: 123.76-827.77 for V + C), peripheral nerve lesion (ROR: 185.64, 95% CI: 73.95-466.03 for V + C), Guillain-Barre syndrome (RORs: 8.80, 2.94, and 11.79, 95% CIs: 3.65-21.22, 1.40-6.19, and 5.87-23.66 for V + C, D + T, and E + B), demyelinating polyneuropathy (RORs: 24.72 and 78.98, 95% CI: 8.16-74.86 and 24.84-251.13 for D + T and E + B), and multiple sclerosis (ROR: 5.90, 95% CI: 3.06-11.40 for D + T) in melanoma patients. nAEs in the setting of BRAFi + MEKi therapy should be a safety consideration when utilizing these medications.

Emerging paradigm: Molecularly targeted therapy with Dabrafenib and Trametinib in recurring pediatric gliomas with BRAF mutations: A narrative review.

Gliomas are tumors arising in the central nervous system, frequently associated with Class I mutations and BRAF fusions. These mutations are adverse prognostic factors in juvenile gliomas, leading to high rates of recurrence and poor response to current treatments. The blood-brain barrier and the heterogeneity of gliomas complicate the development of a single treatment strategy for all cases. This review aims to evaluate the efficacy and safety of combination therapies, particularly Dabrafenib and Trametinib, in pediatric gliomas with BRAF V600 mutations and discusses their potential in improving clinical outcomes. A review of recent clinical trials was conducted to assess the impact of targeted therapies, especially the combination of Dabrafenib and Trametinib, on glioma treatment outcomes. Additional therapies are also explored. Combination therapy with Dabrafenib, a BRAF kinase inhibitor, and Trametinib, a MEK inhibitor, has shown significant improvement in overall survival and progression-free survival for pediatric patients with BRAF V600-mutant gliomas. Recent clinical data from 2023 demonstrated enhanced tumor control, reduced relapse rates, and improved safety profiles compared to conventional therapies. Dabrafenib and Trametinib offer a promising targeted therapy for juvenile gliomas with BRAF V600 mutations, with better survival outcomes and manageable safety profiles. However, challenges remain in managing side effects such as fever, headache, lethargy, and rash. Further research into resistance mechanisms and long-term effects is necessary to optimize treatment strategies. Other therapies, such as everolimus and Selumetinib, also show potential and warrant further investigation.

Comparative study of Bupivacaine with magnesium sulfate versus bupivacaine with dexmedetomidine in peripheral nerve stimulator-guided transversus abdominis plane block for post-operative analgesia in cesarean section

Background: Magnesium sulfate and dexmedetomidine can be used as an adjuvant to local anesthetic solutions to enhance the quality and duration of peripheral nerve blocks. Aims and Objective: The objective was to compare magnesium sulfate and dexmedetomidine as adjuvants to bupivacaine (0.25%) in a transversus abdominis plane (TAP) block using a peripheral nerve stimulator (PNS) for post-operative pain relief in parturients undergoing caesarean delivery. Materials and Methods: A total of 150 pregnant women of ASA Grade I and II in the age range of 18–40, underwent elective cesarean delivery under the subarachnoid block, were divided into three groups of 50 each: Group A (bupivacaine and normal saline), Group B (bupivacaine and MgSO4), and Group C (bupivacaine and dexmedetomidine). Following caesarean delivery, all participants went through a bilateral PNS guided TAP block utilizing one of the treatment techniques. At 0 h, 2 h, 4 h, 6 h, 12 h, 24 h, and 48 h, all patients were monitored for pain, hemodynamic parameters, and side effects. Results: The present study was carried out on 60 patients of thyroid lesions, out of which 21 cases were benign and 39 cases were malignant lesions. Correlation between ICC and reverse transcription-polymerase chain reaction (RT-PCR), a significant correlation was observed between ICC and RT-PCR for BRAF mutation (P&lt;0.001). As per location of tumor is concerned, no significant correlation was observed with BRAF through ICC (P&gt;0.001). The total concordance between ICC and quantitative RT-PCR was 96.8% (Pearson Chi-square test P-value is less than the significance level (0.05), which was statistical significant (P&lt;0.001). The sensitivity and specificity of BRAF ICC on cellblock in malignant thyroid lesions was 76.9% and 100%, respectively. The sensitivity and specificity of BRAF RT-PCR on cellblock in malignant thyroid lesions was 79.4% and 100%, respectively. The sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy of combined BRAF ICC with RT-PCR was 96.8%, 100%, 100%, 90%, and 97.5%, respectively, on cellblock in malignant thyroid lesions. Conclusion: Dexmedetomidine and magnesium sulfate can be safely used as an adjuvant to bupivacaine (0.25%) to prolong the duration of pain relief while reducing the consumption of other analgesics without significant side effects.

Evaluating the Implementation and Impact of BRAF Reflex Mutation Testing in Melanoma, Lung, and Colorectal Cancers.

Reflex molecular testing, the process of profiling specimens at diagnosis, is emerging in oncology, allowing for prompt therapy initiation, and potentially improving outcomes. This study evaluates the impact of reflex BRAF testing on treatment timelines and outcomes in melanoma, lung and colorectal cancers at the McGill University Health Center (MUHC). A retrospective chart review was conducted at the MUHC. The study included patients with melanoma, lung, and colorectal cancers who underwent BRAF testing from 2017 to 2022. Data on demographics, cancer type, stage, test ordering specialist, testing method, and treatment outcomes were extracted. Statistical analyses included descriptive and multivariate regression analyses. 518 BRAF molecular tests were performed, with 173 patients meeting the inclusion criteria [median age 72 (IQR 60-80 years), 46.2% female]. Of these, 75.7% had melanoma, 23.7% colorectal cancer and 0.58% lung cancer. Pathologists ordered 71.1% of BRAF tests, primarily relying on immunohistochemistry. By 2022, all BRAF results were available before oncology consultations. Patients with pre-consultation BRAF results were more likely to receive targeted therapy (59.4% vs 36.4%). The availability of BRAF test results was associated with quicker treatment initiation and better alignment of therapy with mutation status. This study underscores the success of the pathology team at MUHC in implementing reflex BRAF mutation testing, enhancing clinical care by ensuring the timely availability of test results. Delays in testing may adversely affect clinical decision-making and therapy selection, highlighting the need for standardized reflex testing protocols across Canada to optimize patient outcomes in melanoma, lung, and colorectal cancers.

First Insight into the Mutational Landscape of BRAF and KRAS Genes in Lung Cancer Patients from Morocco

Background: Lung cancer (LC) is a lethal malignancy with a late diagnosis and poor prognosis. During the last decade, the identification of oncogenic driver alterations has noticeably changed the therapeutic landscape and contributed to the emergence of the “oncogene addiction” concept and precision medicine in oncology. Among these alterations, the spotlight has turned to driver mutations in the KRAS and BRAF genes, which have garnered significant attention due to the emergence of targeted therapies and the potential for personalized treatment strategies. Objective: Hence, the present study aimed to evaluate the mutational landscape of the KRAS and BRAF genes in LC Moroccan patients along with their frequencies and their correlation with clinicopathological features. Methods: A total of 60 fresh biopsies were collected from patients with primary LC and were subjected to PCR-DNA sequencing of exon 2 of KRAS and exon 15 of BRAF genes in order to detect the most common mutations known by their implication in response to targeted therapies. Results: Sequencing analysis revealed that mutations in KRAS and BRAF genes represented respectively 8.3% and 6.7% of cases; one patient had two KRAS mutations (G12A and K5E), and none had simultaneous BRAF and KRAS mutations. The vast majority of patients harboring KRAS mutations were men, formal smokers with adenocarcinomas, and at advanced stage (stage III). BRAF mutations were mainly detected in men and nonsmokers with adenocarcinoma. Statistical analyses showed no significant correlation between KRAS and BRAF substitutions and clinico-pathological features (p&gt;0.05). Conclusion: The presence of these mutations will be used as a valuable molecular biomarker to select potential candidates eligible for effective personalized medicine using available agents targeting these mutations. Much effort is needed to identify other druggable mutations to generalize personalized LC therapy for better management of this devastating disease.

Prognostic and Molecular Characterization of Metastatic Transverse Colon Cancer: Insights From a Single-Center Retrospective Study.

Metastatic transverse colon cancer (TCC) represents a unique subset of colorectal cancer with features of both right and left colon tumors due to its distinct embryologic origin. This study retrospectively analyzes the clinical, pathological, and molecular factors influencing survival outcomes in TCC patients treated at a single center. For this study, we reviewed the files of 372 metastatic patients and analyzed the data of 71 patients with a diagnosis of TCC in detail. The remaining patients were patients with right or left colon tumors and we compared the overall survival (OS), molecular mutations (KRAS, NRAS, BRAF, MSI status), and clinicopathological features of our patients with transverse colon tumors with these patients. The median OS for TCC patients was 19.7 months, with metastasectomy and Eastern Cooperative Oncology Group (ECOG) performance status emerging as significant prognostic factors. Molecular analyses revealed KRAS mutations in 49% and BRAF mutations in 13% of TCC cases, aligning TCC closer to right-sided tumors in certain molecular characteristics. However, histopathologic diversity, including mucinous histology in 20% of TCC cases, indicated a need to consider TCC as a distinct entity. These findings underscore the complex biological nature of TCC and the necessity for tailored therapeutic approaches, especially as survival rates remain suboptimal. Further multicenter, prospective studies are recommended to establish refined treatment strategies for TCC patients.

Braf-Mutant Melanomas: Biology and Therapy.

The incidence of melanoma, the most lethal form of skin cancer, has increased mainly due to ultraviolet exposure. The molecular characterization of melanomas has shown a high mutational burden led to the identification of some recurrent genetic alterations. BRAF gene is mutated in 40-50% of melanomas and its role in melanoma development is paramount. BRAF mutations confer constitutive activation of MAPK signalling. The large majority (about 90%) of BRAF mutations occur at amino acid 600; the majority are BRAFV600E mutations and less frequently BRAFv600K, V600D and V600M. The introduction of drugs that directly target BRAF-mutant protein (BRAF inhibitors) and of agents that stimulate immune response through targeting of immune check inhibitor consistently improved the survival of melanoma BRAFV600-mutant patients with unresectable/metastatic disease. In parallel, studies in melanoma stage II-III patients with resectable disease have shown that adjuvant therapy with ICIs and/or targeted therapy improves PFS and RFS, but not OS compared to placebo; however, neoadjuvant therapy plus adjuvant therapy improved therapeutic response compared to adjuvant therapy alone.

Navigating Therapeutic Challenges in BRAF-Mutated NSCLC: Non-V600 Mutations, Immunotherapy, and Overcoming Resistance.

Although rare in non-small cell lung cancer (NSCLC), BRAF mutations present considerable therapeutic challenges. While the use of BRAF and MEK inhibitor combinations has significantly improved survival outcomes in patients with BRAF V600E mutations, no targeted therapies are currently available for class II and III mutations, leaving the optimal treatment strategy and prognosis for these patients uncertain. Additionally, despite immunotherapy typically showing limited benefit in patients with other activating genomic alterations, it appears to deliver comparable efficacy in BRAF-mutated NSCLC, emerging as a potentially viable treatment option, particularly in patients with a history of smoking. However, resistance to BRAF pathway inhibitors is inevitable, leading to disease progression, and a well-defined strategy to overcome these resistance mechanisms is lacking. This review aims to explore the critical challenges in the management of BRAF-mutated NSCLC, providing a comprehensive summary of the current evidence and highlighting ongoing clinical trials that aim to address these critical gaps.

A powerful framework for differential co-expression analysis of general risk factors.

Differential co-expression analysis (DCA) aims to identify genes in a pathway whose shared expression depends on a risk factor. While DCA provides insights into the biological activity of diseases, existing methods are limited to categorical risk factors and/or suffer from bias due to batch and variance-specific effects. We propose a new framework, Kernel-based Differential Co-expression Analysis (KDCA), that harnesses correlation patterns between genes in a pathway to detect differential co-expression arising from general (i.e., continuous, discrete, or categorical) risk factors. Using various simulated pathway architectures, we find that KDCA accounts for common sources of bias to control the type I error rate while substantially increasing the power compared to the standard eigengene approach. We then applied KDCA to The Cancer Genome Atlas thyroid data set and found several differentially co-expressed pathways by age of diagnosis and BRAF mutation status that were undetected by the eigengene method. Collectively, our results demonstrate that KDCA is a powerful testing framework that expands DCA applications in expression studies.

Beyond BRAFV600E: Investigating the Clinical and Genetic Spectrum of Langerhans Cell Histiocytosis in Children.

Langerhans cell histiocytosis (LCH) is the most prevalent histiocytic disorder in pediatric populations, with a highly heterogeneous clinical presentation. Currently, the correlation between clinical phenotypes and molecular alterations in childhood LCH, besides the BRAFV600E mutation, has not been sufficiently studied. This study presented data on 33 pediatric LCH patients treated at our center who exhibited various molecular alterations other than the BRAFV600E mutation. Additionally, we comprehensively reviewed pediatric LCH cases with non-BRAFV600E molecular alterations reported from January 2010 to August 2024. A total of 309 pediatric LCH patients with molecular alterations beyond BRAFV600E were enrolled in the study, among whom 33 were from our center. In these LCH cases, 49 kinds of MAP2K1 mutations, 31 kinds of BRAF mutations, and 4 kinds of ARAF mutations were found. At our center, two patients with multisystem LCH with risk organ involvement, both with BRAFN486_P490del mutation, showed poor response to induction chemotherapy for 6 weeks. Among the 303 LCH patients with MAP2K1 or other BRAF alterations, patients with the MAP2K1 mutation had a higher prevalence of single-system bone involvement (SS-bone) than patients carrying the BRAF mutation (p = 0.0072). Within the MAP2K1 group, exon 3 mutations exhibited a stronger association with SS-bone than exon 2 mutations (p = 0.042). Additionally, patients with the BRAF exon 15 mutation and MAP2K1 exon 2 mutation had higher rates of LCH onset before age 3 compared with patients carrying the BRAF exon 12 mutation and MAP2K1 exon 3 mutation (p = 0.037; p = 0.0015). Patients carrying the BRAF mutation in exon 15 had higher rates of liver involvement compared with patients carrying the exon 12 (p = 0.042). Pediatric LCH patients often carry recurrent somatic MAP2K1 and BRAF mutations, which are associated with clinical manifestations.