1. Malignant Melanoma: Skin Cancer-Diagnosis, Prevention, and Treatment.
作者:Ahmed Bilal , Qadir Muhammad Imran , Ghafoor Saba
期刊:Critical reviews in eukaryotic gene expression
日期:2020-01-01
DOI :10.1615/CritRevEukaryotGeneExpr.2020028454
Melanoma is a skin cancer caused by a malignancy of melanocytes. Incidence of melanoma is rapidly increasing worldwide, which results in public health problems. Primary extracutaneous melanomas can be ocular, gastrointestinal, mucosal, leptomeningeal, genitourinary, and lymphatic. The relationship between exposure to ultraviolet (UV) light and development of melanoma is intensively acute and complex, and intermittent sun exposure greatly increases the risk of melanoma. It is the fifth most common type of cancer in men number and the sixth most common in women. The diagnosis of melanoma is made through clinical assessment of the pigmented by health care professionals. Architectural features of malignant melanoma including asymmetry, confluence of growth, marked cellularity, and poor circumscription. The cytological feature of malignant melanoma include an irregular and thick nuclear membrane and prominent nucleoli. The preventive measures include reducing exposure to UV light and the sun. The early detection of skin cancer greatly reduces both short- and long-term morbidity and mortality. The treatment and follow-up with the doctor for melanoma patients may differ because of the stage of the tumor and the primary lesion. The typical therapy for malignant melanoma is surgical excision, immunotherapy such as interleukin 2 (IL-2), gene therapy, and biochemotherapy.
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1区Q1影响因子: 7.1
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2. The concepts of rechallenge and retreatment in melanoma: A proposal for consensus definitions.
作者:Gebhardt Christoffer , Ascierto Paolo , Atkinson Victoria , Corrie Pippa , Dummer Reinhard , Schadendorf Dirk
期刊:European journal of cancer (Oxford, England : 1990)
日期:2020-08-26
DOI :10.1016/j.ejca.2020.07.016
Patients with BRAF-mutant melanoma commonly develop resistance to BRAF inhibitor and MEK inhibitor (BRAF/MEKi) treatment, resulting in disease recurrence or progression. Repeated treatment after a break or an intervening therapy may provide clinical benefit. To ensure a common understanding when discussing the treatment of BRAF-mutant melanoma, we propose consensus definitions for retreatment and rechallenge. 'Retreatment' should be defined as 'repeated treatment with the same therapeutic class following relapse after adjuvant treatment has ended.' Retreatment may be an option for patients with unresectable or metastatic disease who have completed prior adjuvant therapy or discontinued adjuvant therapy early due to toxicity or patients with locoregional recurrence after adjuvant treatment who subsequently underwent resection. 'Rechallenge' should be defined as 'repeated treatment with the same therapeutic class following disease progression in patients who had clinical benefit with prior treatment for unresectable or metastatic disease.' Rechallenge may be an option for patients who had disease progression after an initial response and received an alternative intervening treatment or patients with unresectable or metastatic melanoma who had a treatment break after responding to BRAF/MEKi therapy. Clinical benefits may be possible with repeated BRAF/MEKi treatment because of the role of the MAPK pathway in melanoma oncogenesis and resistance mechanisms specific to BRAF/MEKi, which are discussed in this article. The concepts of retreatment and rechallenge may also be relevant for treatment with immune checkpoint inhibitors in patients with melanoma. Use of consistent terminology will help to stimulate and align further research in this area.
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3区Q2影响因子: 4.4
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3. BRAF Mutations in Melanoma: Biological Aspects, Therapeutic Implications, and Circulating Biomarkers.
期刊:Cancers
日期:2023-08-08
DOI :10.3390/cancers15164026
Melanoma is an aggressive form of skin cancer resulting from the malignant transformation of melanocytes. Recent therapeutic approaches, including targeted therapy and immunotherapy, have improved the prognosis and outcome of melanoma patients. BRAF is one of the most frequently mutated oncogenes recognised in melanoma. The most frequent oncogenic BRAF mutations consist of a single point mutation at codon 600 (mostly V600E) that leads to constitutive activation of the BRAF/MEK/ERK (MAPK) signalling pathway. Therefore, mutated BRAF has become a useful target for molecular therapy and the use of BRAF kinase inhibitors has shown promising results. However, several resistance mechanisms invariably develop leading to therapeutic failure. The aim of this manuscript is to review the role of BRAF mutational status in the pathogenesis of melanoma and its impact on differentiation and inflammation. Moreover, this review focuses on the mechanisms responsible for resistance to targeted therapies in BRAF-mutated melanoma and provides an overview of circulating biomarkers including circulating tumour cells, circulating tumour DNA, and non-coding RNAs.
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3区Q1影响因子: 3.9
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4. Construction of a novel prognostic model in skin cutaneous melanoma based on chemokines-related gene signature.
期刊:Scientific reports
日期:2023-10-24
DOI :10.1038/s41598-023-44598-2
Skin cutaneous melanoma, SKCM, is one of the most aggressive treatment-resistant tumours. Despite the fact that the BRAF oncogene and immunological checkpoints such as PD-1/PD-L1 and CTLA-4 have enhanced the therapeutic efficacy of SKCM, the subsequent resistance mechanisms and remedies have raised concerns. Chemokines have a significant role in the immunological milieu of tumor, which may increase the efficacy of checkpoint blockade and serve as a possible therapeutic intervention route. However, there is still no chemokine-based typing and risk model to provide a prognosis and therapeutic efficacy assessment for SKCM patients. In this study, we verified the distinct differences of prognostic stratification as well as immune characteristics between two chemokine-related clusters in SKCM patients. Two clusters of DEGs were discovered to be primarily enriched in B and T cell receptor signaling pathways as well as TNF signaling via NF-kappa-B. Based on 14 prognosis-related DEGs from aforementioned two clusters (CCL8, GBP2, GBP4, SRNG, HLA-DMB, RARRES3, HLA-DQA1, PARP12, APOL3, IRF1, HLA-DRA, UBE2L6, IL2RA and CD38), a chemokine-related 14-gene prognostic model was established. At the same time, researchers explored differences between the low-risk and high-risk groups in clinical traits, the proportion of infiltration of 22 different types of immune cells, and how well medications worked. The risk score model's immunotherapy and prognostic predictions were also confirmed in testing groups. Based on the finding, we can claim that there is a clear link between chemokines and TME in SKCM. The risk score may perform as a trustworthy prediction model, giving therapeutic benefits for both chemotherapy and immunotherapy, as well as being beneficial for clinical decision making in SKCM patients.
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3区Q1影响因子: 3.9
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5. Cancer systems biology of TCGA SKCM: efficient detection of genomic drivers in melanoma.
期刊:Scientific reports
日期:2015-01-20
DOI :10.1038/srep07857
We characterized the mutational landscape of human skin cutaneous melanoma (SKCM) using data obtained from The Cancer Genome Atlas (TCGA) project. We analyzed next-generation sequencing data of somatic copy number alterations and somatic mutations in 303 metastatic melanomas. We were able to confirm preeminent drivers of melanoma as well as identify new melanoma genes. The TCGA SKCM study confirmed a dominance of somatic BRAF mutations in 50% of patients. The mutational burden of melanoma patients is an order of magnitude higher than of other TCGA cohorts. A multi-step filter enriched somatic mutations while accounting for recurrence, conservation, and basal rate. Thus, this filter can serve as a paradigm for analysis of genome-wide next-generation sequencing data of large cohorts with a high mutational burden. Analysis of TCGA melanoma data using such a multi-step filter discovered novel and statistically significant potential melanoma driver genes. In the context of the Pan-Cancer study we report a detailed analysis of the mutational landscape of BRAF and other drivers across cancer tissues. Integrated analysis of somatic mutations, somatic copy number alterations, low pass copy numbers, and gene expression of the melanogenesis pathway shows coordination of proliferative events by Gs-protein and cyclin signaling at a systems level.
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3区Q2影响因子: 2.8
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6. Data-driven analysis to identify prognostic immune-related biomarkers in BRAF mutated cutaneous melanoma microenvironment.
期刊:Frontiers in genetics
日期:2022-11-30
DOI :10.3389/fgene.2022.1081418
Skin cutaneous melanoma is one of the deadly diseases, and more than 50% of the patients have BRAF gene mutations. Evidence suggests that oncogenic BRAF modulates the immune system's ability to recognize SKCM cells. Due to the complexity of the tumor microenvironment (TME) and a lack of a rational mechanistic basis, it is urgent to investigate the immune infiltration and identify prognostic biomarkers in BRAF mutated SKCM patients. Multiple methods including ESTIMATE algorithm, differential gene analysis, prognostic analysis and immune infiltration analysis were performed to investigate the tumor microenvironment. Based on the patient's immune score and stromal score, immune-related genes DEGs were identified. Functional analysis revealed that these genes were mainly enriched in biological processes such as immune response, defense response and positive regulation of immune system. Furthermore, we analyzed the immune infiltrating cell components of BRAF mutated patients and revealed 4 hub genes associated with overall survival time. Several cells (Monocyte, Macrophage and Gamma delta cells) have been found to be significantly decreased in immune-high BRAF mutated SKCM group. While CD4T, CD8T, CD4 naïve, Tr1, Th2 and many T cell subsets were significantly increased in immune-high group. These immune cells and genes were closely related to each other. This study revealed that the dysregulation of immune function and immune cells may contribute to the poor outcomes of BRAF mutated patients. It is of great significance to our further understanding of the TME and immune dysfunction in BRAF mutated SKCM.
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1区Q1影响因子: 9.6
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7. GJB5 association with BRAF mutation and survival in cutaneous malignant melanoma.
期刊:The British journal of dermatology
日期:2021-10-10
DOI :10.1111/bjd.20629
BACKGROUND:Gap-junctional intercellular communication is crucial for epidermal cellular homeostasis. Inability to establish melanocyte-keratinocyte contact and loss of the intercellular junction's integrity may contribute to melanoma development. Connexins, laminins and desmocollins have been implicated in the control of melanoma growth, where their reduced expression has been reported in metastatic lesions. OBJECTIVES:The aim of this study was to investigate connexin 31·1 (GJB5) expression and identify any association with BRAF mutational status, prognosis of patients with melanoma and mitogen-activated protein kinase (MAPK) inhibitor (MAPKi) treatment. METHODS:GJB5 expression was measured at RNA and protein level in melanoma clinical samples and established cell lines treated (or not) with BRAF and MEK inhibitors (MEKi), as well as in cell lines which developed MAPKi resistance. Findings were further validated and confirmed by analysis of independent datasets. RESULTS:Our analysis reveals significant downregulation of GJB5 expression in metastatic melanoma lesions compared with primary ones and in BRAF-mutated vs. BRAF-wildtype (BRAF ) melanomas. Likewise, GJB5 expression is significantly lower in BRAF compared with BRAF cell lines and increases on MAPKi treatment. MAPKi-resistant melanoma cells display a similar expression pattern compared with BRAF cells, with increased GJB5 expression associated with morphological changes. Enhancement of BRAF expression in BRAF melanoma cells significantly upregulates miR-335-5p expression with consequent downregulation of GJB5, one of its targets. Furthermore, overexpression of miR-335-5p in two BRAF cell lines confirms specific GJB5 protein downregulation. Reverse transcriptase quantitative polymerase chain reaction analysis also revealed upregulation of miR-335 in BRAF melanoma cells, which is significantly downregulated in cells resistant to MEKi. Our data were further validated using the TCGA_SKCM dataset, where BRAF mutations associate with increased miR-335 expression and inversely correlate with GJB5 expression. In clinical samples, GJB5 underexpression is also associated with patient overall worse survival, especially at early stages. CONCLUSIONS:We identified a significant association between metastases/BRAF mutation and low GJB5 expression in melanoma. Our results identify a novel mechanism of gap-junctional protein regulation, suggesting a prognostic role for GJB5 in cutaneous melanoma.
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1区Q1影响因子: 48.5
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8. Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.
期刊:Nature
日期:2017-08-02
DOI :10.1038/nature23291
Approximately 200 BRAF mutant alleles have been identified in human tumours. Activating BRAF mutants cause feedback inhibition of GTP-bound RAS, are RAS-independent and signal either as active monomers (class 1) or constitutively active dimers (class 2). Here we characterize a third class of BRAF mutants-those that have impaired kinase activity or are kinase-dead. These mutants are sensitive to ERK-mediated feedback and their activation of signalling is RAS-dependent. The mutants bind more tightly than wild-type BRAF to RAS-GTP, and their binding to and activation of wild-type CRAF is enhanced, leading to increased ERK signalling. The model suggests that dysregulation of signalling by these mutants in tumours requires coexistent mechanisms for maintaining RAS activation despite ERK-dependent feedback. Consistent with this hypothesis, melanomas with these class 3 BRAF mutations also harbour RAS mutations or NF1 deletions. By contrast, in lung and colorectal cancers with class 3 BRAF mutants, RAS is typically activated by receptor tyrosine kinase signalling. These tumours are sensitive to the inhibition of RAS activation by inhibitors of receptor tyrosine kinases. We have thus defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway.
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1区Q1影响因子: 15.7
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9. Targeting melanoma's MCL1 bias unleashes the apoptotic potential of BRAF and ERK1/2 pathway inhibitors.
期刊:Nature communications
日期:2019-11-14
DOI :10.1038/s41467-019-12409-w
BRAF and MEK1/2 inhibitors are effective in melanoma but resistance inevitably develops. Despite increasing the abundance of pro-apoptotic BIM and BMF, ERK1/2 pathway inhibition is predominantly cytostatic, reflecting residual pro-survival BCL2 family activity. Here, we show that uniquely low BCL-X expression in melanoma biases the pro-survival pool towards MCL1. Consequently, BRAF or MEK1/2 inhibitors are synthetic lethal with the MCL1 inhibitor AZD5991, driving profound tumour cell death that requires BAK/BAX, BIM and BMF, and inhibiting tumour growth in vivo. Combination of ERK1/2 pathway inhibitors with BCL2/BCL-w/BCL-X inhibitors is stronger in CRC, correlating with a low MCL1:BCL-X ratio; indeed the MCL1:BCL-X ratio is predictive of ERK1/2 pathway inhibitor synergy with MCL1 or BCL2/BCL-w/BCL-X inhibitors. Finally, AZD5991 delays acquired BRAFi/MEKi resistance and enhances the efficacy of an ERK1/2 inhibitor in a model of acquired BRAFi + MEKi resistance. Thus combining ERK1/2 pathway inhibitors with MCL1 antagonists in melanoma could improve therapeutic index and patient outcomes.