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1.
Int J Mol Sci ; 22(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198843

RESUMO

Vitreoretinal lymphoma (VRL) is an uncommon eye malignancy, and VRLs of T cell origin are rare. They are difficult to treat, and their molecular underpinnings, including actionable genomic alterations, remain to be elucidated. At present, vitreous fluid liquid biopsies represent a valuable VRL sample for molecular analysis to study VRLs. In this study, we report the molecular diagnostic workup of a rare case of bilateral T cell VRL and characterize its genomic landscape, including identification of potentially targetable alterations. Using next-generation sequencing of vitreous-derived DNA with a pan-cancer 126-gene panel, we found a copy number gain of BRAF and copy number loss of tumor suppressor DNMT3A. To the best of our knowledge, this represents the first exploration of the T cell VRL cancer genome and supports vitreous liquid biopsy as a suitable approach for precision oncology treatments.


Assuntos
DNA (Citosina-5-)-Metiltransferases/genética , Linfoma de Células T/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias da Retina/genética , Biomarcadores Tumorais/genética , Variações do Número de Cópias de DNA/genética , Regulação Neoplásica da Expressão Gênica/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Biópsia Líquida , Linfoma de Células T/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Neoplasias da Retina/patologia , Corpo Vítreo/metabolismo , Corpo Vítreo/patologia
2.
Int J Mol Sci ; 22(11)2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34204950

RESUMO

The dysregulation of autophagy is important in the development of many cancers, including thyroid cancer, where V600EBRAF is a main oncogene. Here, we analyse the effect of V600EBRAF inhibition on autophagy, the mechanisms involved in this regulation and the role of autophagy in cell survival of thyroid cancer cells. We reveal that the inhibition of V600EBRAF activity with its specific inhibitor PLX4720 or the depletion of its expression by siRNA induces autophagy in thyroid tumour cells. We show that V600EBRAF downregulation increases LKB1-AMPK signalling and decreases mTOR activity through a MEK/ERK-dependent mechanism. Moreover, we demonstrate that PLX4720 activates ULK1 and increases autophagy through the activation of the AMPK-ULK1 pathway, but not by the inhibition of mTOR. In addition, we find that autophagy blockade decreases cell viability and sensitize thyroid cancer cells to V600EBRAF inhibition by PLX4720 treatment. Finally, we generate a thyroid xenograft model to demonstrate that autophagy inhibition synergistically enhances the anti-proliferative and pro-apoptotic effects of V600EBRAF inhibition in vivo. Collectively, we uncover a new role of AMPK in mediating the induction of cytoprotective autophagy by V600EBRAF inhibition. In addition, these data establish a rationale for designing an integrated therapy targeting V600EBRAF and the LKB1-AMPK-ULK1-autophagy axis for the treatment of V600EBRAF-positive thyroid tumours.


Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas Quinases/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias da Glândula Tireoide/genética , Apoptose/efeitos dos fármacos , Autofagia/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Indóis/farmacologia , Mutação/genética , Inibidores de Proteínas Quinases/farmacologia , RNA Interferente Pequeno/genética , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/patologia
3.
Gan To Kagaku Ryoho ; 48(7): 861-865, 2021 Jul.
Artigo em Japonês | MEDLINE | ID: mdl-34267017

RESUMO

BRAF mutation is occurred in about 8% of human malignancy, including 40-60% in malignant melanoma, 50% in thyroid papillary cancer, 10% in colorectal cancer, and a few percent of non-small cell lung cancer. Activated mutation of BRAF is mainly p. V600E mutation. BRAF inhibitors were initially developed in malignant melanoma. In a recent few years, BRAF inhibitor-based therapy has been developed also in other cancers such as lung cancer and colorectal cancer. I herein describe the current status of development of new therapeutic strategies for BRAF-mutated cancer, particularly BRAF-targeting therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Melanoma , Neoplasias da Glândula Tireoide , Humanos , Mutação , Proteínas Proto-Oncogênicas B-raf/genética
4.
Hematol Oncol ; 39 Suppl 1: 15-23, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34105821

RESUMO

Children with Langerhnans cell histiocytosis (LCH) develop granulomatous lesions with characteristic clonal CD207+ dendritic cells that can arise as single lesions or life-threatening disseminated disease. Despite the wide range of clinical presentations, LCH lesions are histologically indistinguishable based on severity of disease, and uncertain classification as an immune versus neoplastic disorder has historically challenged the development of optimal clinical strategies for patients with LCH. Recently, activating somatic mutations in MAPK pathway genes, most notably BRAFV600E, have been discovered in almost all cases of LCH. Further, the stage of myeloid differentiation in which the mutation arises defines the extent of disease and risk of developing LCH-associated neurodegeneration. MAPK activation in LCH precursor cells drives myeloid differentiation, inhibits migration, and inhibits apoptosis, resulting in accumulation of resilient pathologic dendritic cells that recruit and activate T cells. Recurrent somatic mutations in MAPK pathway genes have also been identified in related histiocytic disorders: juvenile xanthogranuloma, Erdheim-Chester disease, and Rosai-Dorfman disease. New insights into pathogenesis support reclassification of these conditions as a myeloid neoplastic disorders. Continued research will uncover opportunities to identify novel targets and inform personalized therapeutic strategies based on cell of origin, somatic mutation, inherited risk factors, and residual disease.


Assuntos
Diferenciação Celular/imunologia , Movimento Celular/imunologia , Células Dendríticas , Histiocitose de Células de Langerhans , Medicina de Precisão , Linfócitos T , Substituição de Aminoácidos , Diferenciação Celular/genética , Movimento Celular/genética , Células Dendríticas/imunologia , Células Dendríticas/patologia , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/imunologia , Histiocitose de Células de Langerhans/patologia , Histiocitose de Células de Langerhans/terapia , Humanos , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/imunologia , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/imunologia , Linfócitos T/imunologia , Linfócitos T/patologia
5.
Int J Mol Sci ; 22(11)2021 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-34073365

RESUMO

Ferroptosis is a new type of programmed cell death, which occurs with iron dependence. Previous studies have showed that ferroptosis plays an important regulatory role in the occurrence and development of tumors. Colon cancer is one of the major morbidities and causes of mortality in the world. This study used RNA-seq and colon cancer clinical data to explore the relationship between ferroptosis-related genes and colon cancer. Based on the fifteen prognostic ferroptosis-related genes, two molecular subgroups of colon cancer were identified. Surprisingly, we also found cluster2 was characterized by lower mutation burden and expression of checkpoint genes, better survival, and higher expression of NOX1. Moreover, cluster2 has fewer BRAF mutations. We also found the expression of NOX1 is related to the status of BRAF. Finally, using 15 ferroptosis-related genes from The Cancer Genome Atlas cohort, we constructed a prognosis model, and this model may be used to predict the prognosis of patients in clinics.


Assuntos
Neoplasias do Colo/metabolismo , Bases de Dados de Ácidos Nucleicos , Ferroptose , Regulação Neoplásica da Expressão Gênica , Modelos Biológicos , NADPH Oxidase 1/biossíntese , Proteínas Proto-Oncogênicas B-raf/biossíntese , Neoplasias do Colo/diagnóstico , Neoplasias do Colo/genética , Humanos , NADPH Oxidase 1/genética , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , RNA-Seq
6.
Nat Commun ; 12(1): 3707, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140478

RESUMO

While the major drivers of melanoma initiation, including activation of NRAS/BRAF and loss of PTEN or CDKN2A, have been identified, the role of key transcription factors that impose altered transcriptional states in response to deregulated signaling is not well understood. The POU domain transcription factor BRN2 is a key regulator of melanoma invasion, yet its role in melanoma initiation remains unknown. Here, in a BrafV600E PtenF/+ context, we show that BRN2 haplo-insufficiency promotes melanoma initiation and metastasis. However, metastatic colonization is less efficient in the absence of Brn2. Mechanistically, BRN2 directly induces PTEN expression and in consequence represses PI3K signaling. Moreover, MITF, a BRN2 target, represses PTEN transcription. Collectively, our results suggest that on a PTEN heterozygous background somatic deletion of one BRN2 allele and temporal regulation of the other allele elicits melanoma initiation and progression.


Assuntos
Carcinogênese/metabolismo , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Genes Supressores de Tumor , Proteínas de Homeodomínio/metabolismo , Melanoma/metabolismo , Fatores do Domínio POU/metabolismo , Neoplasias Cutâneas/metabolismo , Animais , Carcinogênese/genética , Linhagem Celular Tumoral , Imunoprecipitação da Cromatina , Estudos de Coortes , Variações do Número de Cópias de DNA , Progressão da Doença , Técnicas de Silenciamento de Genes , Haploinsuficiência , Proteínas de Homeodomínio/genética , Humanos , Imuno-Histoquímica , Melanoma/genética , Melanoma/mortalidade , Melanoma/secundário , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Análise em Microsséries , Fator de Transcrição Associado à Microftalmia/metabolismo , Mutação , Fatores do Domínio POU/genética , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , RNA Interferente Pequeno , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/secundário
7.
BMJ Case Rep ; 14(6)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34167970

RESUMO

A woman in her 40s presented to the emergency department with headache and unintentional weight loss in September 2018. Investigations revealed a widely metastatic pan-negative melanoma of unknown primary. She had multiple lines of treatment including combination immunotherapy and chemotherapy. Next-generation sequencing identified an SKAP2-BRAF fusion protein, and she was commenced on an MEK inhibitor in September 2019 with a partial response seen on restaging scans after 6 weeks and a dramatic fall in her lactate dehydrogenase from 2248 IU/L to 576 IU/L. Unfortunately, the response was not maintained and she died from progression of her cancer in January 2020. SKAP2-BRAF fusions have a dimerisation domain that paradoxically activates the mitogen-activated protein kinase pathway, resulting in hyperproliferation if first-generation or second-generation BRAF inhibitors are used. Our knowledge is limited regarding the complex effects of targeted therapy in rare BRAF fusion proteins.


Assuntos
Melanoma , Neoplasias Cutâneas , Feminino , Humanos , Imunoterapia , Melanoma/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética
8.
Gan To Kagaku Ryoho ; 48(6): 787-795, 2021 Jun.
Artigo em Japonês | MEDLINE | ID: mdl-34139726

RESUMO

Precision medicine, which considers the genetics of the tumor tissues and cells for selection of the most appropriate treatment strategy, has recently been developed for colorectal cancer. The BRAF mutation status in colorectal cancer has been tested, but precision medicine for BRAF-mutated tumors had not been applicable due to no approved BRAF-targeting drugs until recently. In addition, conventional standard chemotherapy for BRAF-mutated colorectal cancer show limited effectiveness, resulting in poor prognosis. Therefore, we need new drugs specific for BRAF-mutated colorectal cancer. In this review, we outline the characteristics, development, and new treatment strategies for BRAF-mutated colorectal cancer. In addition, we introduce the BEACON CRC study, which prospectively evaluated the efficacy and safety of combination therapy of encorafenib(BRAF inhibitor), binimetinib(MEK inhibitor), and cetuximab(anti-EGFR antibody)in patients with metastatic colorectal cancer with the BRAF V600E-mutation.


Assuntos
Neoplasias Colorretais , Proteínas Proto-Oncogênicas B-raf , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Humanos , Mutação , Proteínas Proto-Oncogênicas B-raf/genética
9.
Magy Onkol ; 65(2): 121-127, 2021 Jun 03.
Artigo em Húngaro | MEDLINE | ID: mdl-34081760

RESUMO

Negative predictive markers of the anti-EGFR antibody therapies are RAS or BRAF mutations, while left sidedness can be considered as a positive predictor. Here we analyzed 97 wild type RAS metastatic colorectal cancers looking for the prognostic and predictive roles of EGFR protein expression. We found that right-sided colorectal cancers are characterized by significantly higher EGFR protein expression as compared to left-sided ones, irrespective of the primary or metastatic tissue analysis. Furthermore, tumors with multiple organ involvement are characterized by significantly higher EGFR protein expression as compared to single organ ones. In the homogenous cetuximab treated cohort (n=90) we have found that lower than the applied EGFR protein expression cut-off was associated with favorable survival. In the multivariate analysis only sidedness proved to be a strong independent predictor, however sidedness is an EGFR-dependent predictor of anti-EGFR therapy.


Assuntos
Neoplasias Colorretais , Cetuximab , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Receptores ErbB/genética , Humanos , Mutação , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética
10.
Magy Onkol ; 65(2): 149-156, 2021 Jun 03.
Artigo em Húngaro | MEDLINE | ID: mdl-34081762

RESUMO

Target-specific inhibition of the BRAFV600E mutant protein has been a major breakthrough in the treatment of metastatic cutaneous melanoma. However, the success of therapies is significantly overshadowed by the development of resistance. Understanding the molecular mechanisms associated with acquired resistance is an important step to increase the effectiveness of melanoma treatment. Our aim was to elucidate the molecular differences underlying the development of drug resistance using a mutant BRAF protein inhibitor (vemurafenib analogue: PLX4720) in BRAFV600E mutant melanoma cell lines. We developed four BRAF inhibitor-resistant cell lines and examined the effect of BRAF inhibitor "withdrawal" on cell division. ArrayCGH was used to define genetic, and Affymetrix HumanGene 1.0 microarray to monitor gene expression alterations between the sensitive and resistant cell lines. Protein expression was determined using Proteome Profiler Human XL Oncology Array. We found that withdrawal of the inhibitor reduces cell proliferation in the resistant cells. The invasive potential of the resistant cells increased. Using genomic and proteomic methods we described new molecular alterations associated with acquired resistance.


Assuntos
Melanoma , Neoplasias Cutâneas , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Mutação , Inibidores de Proteínas Quinases/farmacologia , Proteômica , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética
11.
Int J Mol Sci ; 22(10)2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-34066022

RESUMO

Melanoma is one of the most aggressive forms of skin cancer and is therapeutically challenging, considering its high mutation rate. Following the development of therapies to target BRAF, the most frequently found mutation in melanoma, promising therapeutic responses were observed. While mono- and combination therapies to target the MAPK cascade did induce a therapeutic response in BRAF-mutated melanomas, the development of resistance to MAPK-targeted therapies remains a challenge for a high proportion of patients. Resistance mechanisms are varied and can be categorised as intrinsic, acquired, and adaptive. RASSF1A is a tumour suppressor that plays an integral role in the maintenance of cellular homeostasis as a central signalling hub. RASSF1A tumour suppressor activity is commonly lost in melanoma, mainly by aberrant promoter hypermethylation. RASSF1A loss could be associated with several mechanisms of resistance to MAPK inhibition considering that most of the signalling pathways that RASSF1A controls are found to be altered targeted therapy resistant melanomas. Herein, we discuss resistance mechanisms in detail and the potential role for RASSF1A reactivation to re-sensitise BRAF mutant melanomas to therapy.


Assuntos
Resistencia a Medicamentos Antineoplásicos , Melanoma/patologia , Inibidores de Proteínas Quinases/farmacologia , Proteínas Supressoras de Tumor/deficiência , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética
12.
Int J Mol Sci ; 22(11)2021 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-34072194

RESUMO

BRAFV600E is the most frequent oncogenic mutation identified in papillary thyroid cancer (PTC). In PTC patients who do not respond to standard treatment, BRAF inhibitors are currently tested as alternative strategies. However, as observed for other targeted therapies, patients eventually develop drug resistance. The mechanisms of BRAF inhibitors response are still poorly understood in a thyroid cancer (TC) context. In this study, we investigated in BRAFV600E mutated TC cell lines the effects of Vemurafenib and Dabrafenib, two BRAF inhibitors currently used in a clinical setting. We assessed cell proliferation, and the expression and activity of the thyroid function related transporter NIS following the treatment with BRAF inhibitors. In addition, we investigated the global gene expression by microarray, the relevant modulated biological processes by gene set enrichment analysis (GSEA), and TC specific gene signatures related to MAPK pathway activation, thyroid differentiation, and transcriptional profile associated with BRAFV600E or RAS mutation. We found that both inhibitors induce antiproliferative and redifferentiative effects on TC cells, as well as a rewiring of the MAPK pathway related to RAS signaling. Our results suggest a possible mechanism of drug response to the BRAF inhibitors Vemurafenib or Dabrafenib, supporting very recent findings in TC patients treated with targeted therapies.


Assuntos
Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Glândula Tireoide/metabolismo , Proteínas ras/metabolismo , Biomarcadores Tumorais , Linhagem Celular Tumoral , Biologia Computacional/métodos , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/etiologia , Neoplasias da Glândula Tireoide/patologia , Transcriptoma
13.
Nat Commun ; 12(1): 3464, 2021 06 08.
Artigo em Inglês | MEDLINE | ID: mdl-34103493

RESUMO

Right-sided (proximal) colorectal cancer (CRC) has a poor prognosis and a distinct mutational profile, characterized by oncogenic BRAF mutations and aberrations in mismatch repair and TGFß signalling. Here, we describe a mouse model of right-sided colon cancer driven by oncogenic BRAF and loss of epithelial TGFß-receptor signalling. The proximal colonic tumours that develop in this model exhibit a foetal-like progenitor phenotype (Ly6a/Sca1+) and, importantly, lack expression of Lgr5 and its associated intestinal stem cell signature. These features are recapitulated in human BRAF-mutant, right-sided CRCs and represent fundamental differences between left- and right-sided disease. Microbial-driven inflammation supports the initiation and progression of these tumours with foetal-like characteristics, consistent with their predilection for the microbe-rich right colon and their antibiotic sensitivity. While MAPK-pathway activating mutations drive this foetal-like signature via ERK-dependent activation of the transcriptional coactivator YAP, the same foetal-like transcriptional programs are also initiated by inflammation in a MAPK-independent manner. Importantly, in both contexts, epithelial TGFß-receptor signalling is instrumental in suppressing the tumorigenic potential of these foetal-like progenitor cells.


Assuntos
Carcinogênese/metabolismo , Neoplasias do Colo/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Receptores de Fatores de Crescimento Transformadores beta/metabolismo , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Carcinogênese/patologia , Diferenciação Celular , Sobrevivência Celular , Colo/patologia , Neoplasias do Colo/genética , Células Epiteliais/metabolismo , Feto/patologia , Inflamação/patologia , Estimativa de Kaplan-Meier , Sistema de Sinalização das MAP Quinases , Camundongos Endogâmicos C57BL , Mutação , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Esferoides Celulares/metabolismo , Esferoides Celulares/patologia , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Proteínas Wnt/metabolismo , Via de Sinalização Wnt
14.
Orphanet J Rare Dis ; 16(1): 272, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34116682

RESUMO

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare neoplastic disease that occurs in both children and adults, and BRAF V600E is detected in up to 64% of the patients. Several studies have discussed the associations between BRAF V600E mutation and clinicopathological manifestations, but no clear conclusions have been drawn regarding the clinical significance of the mutation in pediatric patients. RESULTS: We retrieved the clinical information for 148 pediatric LCH patients and investigated the BRAF V600E mutation using next-generation sequencing alone or with droplet digital PCR. The overall positive rate of BRAF V600E was 60/148 (41%). The type of sample (peripheral blood and formalin-fixed paraffin-embedded tissue) used for testing was significantly associated with the BRAF V600E mutation status (p-value = 0.000 and 0.000). The risk of recurrence declined in patients who received targeted therapy (p-value = 0.006; hazard ratio 0.164, 95%CI: 0.046 to 0.583). However, no correlation was found between the BRAF V600E status and gender, age, stage, specific organ affected, TP53 mutation status, masses close to the lesion or recurrence. CONCLUSIONS: This is the largest pediatric LCH study conducted with a Chinese population to date. BRAF V600E in LCH may occur less in East Asian populations than in other ethnic groups, regardless of age. Biopsy tissue is a more sensitive sample for BRAF mutation screening because not all of circulating DNA is tumoral. Approaches with low limit of detection or high sensitivity are recommended for mutation screening to avoid type I and II errors.


Assuntos
Histiocitose de Células de Langerhans , Proteínas Proto-Oncogênicas B-raf , Adulto , Criança , Estudos de Coortes , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação , Proteínas Proto-Oncogênicas B-raf/genética
15.
Arq Bras Cir Dig ; 34(1): e1574, 2021.
Artigo em Inglês, Português | MEDLINE | ID: mdl-34133521

RESUMO

BACKGROUND: Inhibitors of the epidermal growth factor (EGFR) represent an effective therapeutic option for patients with metastatic colorectal carcinoma, free of activating mutations in KRAS and NRAS. However, the research of mutations is of high cost and scarcely accessible. The expression of the EGFR by immunohistochemistry predicting the mutation status of the expanded RAS (KRAS and NRAS), may allow treatment by a diagnostic method less costly and more accessible. AIM: Investigate the correlation between the clinical-pathological data, the cytoplasmic-membrane expression of the EGFR and the mutational status of the expanded RAS. METHOD: A total of 139 patients with colorectal carcinoma from the archives of Instituto Goiano de Oncologia e Hematologia were evaluated. RESULTS: Mutation of the expanded RAS was detected in 78 (56.1%) cases. The EGFR expression was stratified in 23 (16.5%) "positive", 49 (35.2%) "negative" and 67 (48.2%) "uncertain". No significant correlation was found between the mutational status of the RAS and the EGFR expression in comparison to age, gender, location, histological type, histological grade and stage. From 23 "positive" cases, 21 (91.3%) showed wild-type RAS gene, and 49 "negative", 41 (83.7%) presented mutation, resulting in a strong association between EGFR "positive", "negative" groups and the mutational status of the RAS (p<0.001), with 86.1% of accuracy. CONCLUSIONS: The cytoplasmic-membrane analysis of the EGFR expression stratified into "positive", "negative" and "uncertain" predicts mutational status of the RAS in 51.7% of the cases (p<0.001), with 86.1% of accuracy.


Assuntos
Neoplasias Colorretais , Proteínas Proto-Oncogênicas B-raf , Neoplasias Colorretais/genética , Fator de Crescimento Epidérmico , Receptores ErbB/genética , Humanos , Mutação , Proteínas Proto-Oncogênicas B-raf/genética
16.
Arch Endocrinol Metab ; 64(6): 751-757, 2021 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-34033285

RESUMO

Objective: Although the prognostic role of BRAFV600E mutation in papillary thyroid carcinoma (PTC) is controversial, the American Thyroid Association (ATA) includes the mutational status in their risk stratification system. To evaluate the impact of the BRAFV600E mutation status on PTC risk stratification. Methods: PTC patients attending a university-based hospital who had the analysis of the BRAFV600E mutation were included. Persistent disease was defined as the presence of biochemical or structural disease. The performance of the ATA risk stratification system on predicting persistent disease with or without the BRAFV600E mutation status information was evaluated. Results: Of the 134 patients evaluated, 44 (32.8%) carried BRAFV600E mutation. The median tumor size was 1.7 cm (P25-75 1.0-3.0), 64 (47.8%) patients had lymph node, and 11 (8.2%) distant metastases. According to the ATA risk stratification system, patients were classified as low, intermediate, and high risk in 55 (41%), 59 (44%), and 20 (14%) patients, respectively. The data on BRAFV600E mutation reclassified 12 (8.9%) patients from low to intermediate risk. After a median follow-up of 8.5 years, the prevalence of persistent disease was similar in patients with and without BRAFV600E mutation (P = 0.42). Multivariate analysis failed to demonstrate an association between the BRAFV600E mutation and persistent disease status (RR 0.96; 95%CI 0.47-1.94). Notably, none of the patients reclassified from low to intermediate risk showed persistent disease on follow-up. Conclusion: Inclusion of BRAFV600E mutational status has a limited impact on risk stratification and does not add to the prediction of outcomes in PTC patients.


Assuntos
Carcinoma Papilar , Carcinoma , Neoplasias da Glândula Tireoide , Carcinoma/genética , Carcinoma Papilar/genética , Humanos , Mutação , Prognóstico , Proteínas Proto-Oncogênicas B-raf/genética , Medição de Risco , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética
17.
Ann Clin Lab Sci ; 51(2): 262-266, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33941568

RESUMO

BRAF and NRAS are oncogenes in the RAS/RAF/MEK/MAP-kinase signaling pathway. Coexistent mutations of BRAF and NRAS in a single colorectal cancer patient have always been considered mutually exclusive or at least rare. The clinical outcome of these patients remains undetermined. Herein we report a 53-year-old man harboring an NRAS Q61L mutation in his primary rectal carcinoma, who presented with a concomitant mutation of BRAF V600E in his liver metastasis biopsy 55 months after the primary CRC surgical resection. Our findings suggest that a BRAF and NRAS developed co-mutation may lead to a distinct clinicopathological progression. BRAF-mutated CRCwill not benefit from anti-RAS targeted therapy.


Assuntos
GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Retais/genética , Análise Mutacional de DNA , GTP Fosfo-Hidrolases/metabolismo , Humanos , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/metabolismo , Transdução de Sinais
18.
Cancer Sci ; 112(7): 2884-2894, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33934428

RESUMO

The BRAF V600E mutation occurs in approximately 10% of patients with metastatic colorectal cancer (CRC) and constitutes a distinct subtype of the disease with extremely poor prognosis. To address this refractory disease, we investigated the unique metabolic gene profile of BRAF V600E-mutated tumors via in silico analysis using a large-scale clinical database. We found that BRAF V600E-mutated tumors exhibited a specific metabolic gene expression signature, including some genes that are associated with poor prognosis in CRC. We discovered that BRAF V600E-mutated tumors expressed high levels of glycolytic enzyme enolase 2 (ENO2), which is mainly expressed in neuronal tissues under physiological conditions. In vitro experiments using CRC cells demonstrated that BRAF V600E-mutated cells exhibited enhanced dependency on ENO2 compared to BRAF wild-type cancer cells and that knockdown of ENO2 led to the inhibition of proliferation and migration of BRAF V600E-mutated cancer cells. Moreover, inhibition of ENO2 resulted in enhanced sensitivity to vemurafenib, a selective inhibitor of BRAF V600E. We identified AP-1 transcription factor subunit (FOSL1) as being involved in the transcription of ENO2 in CRC cells. In addition, both MAPK and PI3K/Akt signaling were suppressed upon inhibition of ENO2, implying an additional oncogenic role of ENO2. These results suggest the crucial role of ENO2 in the progression of BRAF V600E-mutated CRC and indicate the therapeutic implications of targeting this gene.


Assuntos
Neoplasias Colorretais/enzimologia , Fosfopiruvato Hidratase/metabolismo , Proteínas Proto-Oncogênicas B-raf/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Movimento Celular/genética , Proliferação de Células/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Bases de Dados Factuais , Progressão da Doença , Ativação Enzimática , Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfopiruvato Hidratase/antagonistas & inibidores , Fosfopiruvato Hidratase/genética , Prognóstico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Interferência de RNA , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismo , Vemurafenib/farmacologia
20.
Bull Cancer ; 108(7-8): 771-778, 2021.
Artigo em Francês | MEDLINE | ID: mdl-34023063

RESUMO

Hairy cell leukemia is a rare form of leukemia: three hundred new cases are diagnosed each year in France. The diagnosis is based on: (1) morphological examination of the blood and bone marrow smear, (2) analysis by flow cytometry of hairy cells, which express three or the four following markers: CD11c, CD25, CD103 and CD123, (3) identification of the BRAFV600E mutation, a true molecular marker of the disease. The management of treatment has evolved considerably in recent years. As of today, the purine analogues remain the standard treatment in the first line. Relapses are however observed in about 40% of cases. In the event of a first relapse, the preferred option is treatment with immunochemotherapy i.e. a combination of cladribine plus rituximab. Subsequent relapses are treated with moxetumomab pasudotox or BRAF inhibitors which provide indisputable benefits if third-line treatment is required. We will discuss in patients with relapsed/refractory hairy cell leukemia the needs for personalized medicine and the advantages and disadvantages of each treatment modality. The good prognosis for LT requires treatments that are not immunosuppressive, non-myelotoxic, and do not increase the risk of secondary cancers.


Assuntos
Leucemia de Células Pilosas/terapia , Doenças Raras/terapia , Antígenos de Neoplasias/análise , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Toxinas Bacterianas/uso terapêutico , Biomarcadores Tumorais/análise , Cladribina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Exotoxinas/uso terapêutico , Humanos , Imunoterapia/métodos , Leucemia de Células Pilosas/diagnóstico , Mansonelose , Mutação , Segunda Neoplasia Primária/prevenção & controle , Pentostatina/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Doenças Raras/diagnóstico , Recidiva , Rituximab/uso terapêutico
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