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1.
Anticancer Res ; 39(10): 5525-5530, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570446

RESUMO

BACKGROUND/AIM: Basal cell carcinoma (BCC) has been genetically associated with an increased expression of angiotensin-converting enzyme (ACE), an important factor of the renin-angiotensin system which produces vasoconstrictor angiotensin II. Other factors of this system include angiotensinogen (AGT) and angiotensin receptors AGTR1, AGTR2. We investigated the possible association of BCC with genetic variability in the AGT, AGTR1 and AGTR2 genes. MATERIALS AND METHODS: DNA samples of 190 Greeks were studied, including 91 patients with BCC and 99 matched healthy controls. Molecular genotyping of patients and controls was performed for the polymorphisms AGT M235T, AGTR1 A1166C and AGTR2 G1675A. RESULTS: The mutant T allele that increases AGT gene expression was detected in two-fold increased frequency in BCC patients in comparison to healthy controls (p <0.001). On the contrary, no significant difference was observed in AGTR1 and AGTR2 variants between patients and controls. CONCLUSION: Increased expression of AGT may be associated with BCC.


Assuntos
Carcinoma Basocelular/genética , Predisposição Genética para Doença/genética , Polimorfismo Genético/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Angiotensinogênio/genética , Estudos de Casos e Controles , Linhagem Celular Tumoral , Feminino , Frequência do Gene/genética , Humanos , Masculino , Pessoa de Meia-Idade , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/genética
2.
Anticancer Res ; 39(10): 5573-5579, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570452

RESUMO

BACKGROUND/AIM: Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine skin cancer, frequently infected with Merkel cell polyomavirus (MCPyV). H3K27me3 acts as a repressive histone modification that epigenetically controls gene transcription. The aim of this study was to examine H3K27me3 expression in MCC. MATERIALS AND METHODS: H3K27me3 expression levels were immunohistochemically analyzed in 20 MCPyV-positive MCCs, 15 MCPyV-negative MCCs with squamous cell carcinoma (SCC) (combined MCCs), and six MCPyV-negative pure MCCs. RESULTS: Reduced H3K27me3 expression was variously observed in MCCs. H3K27me3 H-score was significantly lower in MCPyV-negative MCCs than in MCPyV-positive MCCs (p=0.002). H3K27me3 expression was significantly lower in MCPyV-negative combined MCC component than in MCPyV-positive MCCs (p<0.001), MCPyV-negative pure MCCs (p=0.036), or pure MCC histology (p<0.001). Kaplan-Meier analysis showed no association of H3K27me3 with outcome. CONCLUSION: Differential reduction in H3K27me3 expression was observed based on MCPyV status and morphological type. These results implicate H3K27me3-mediated epigenetic changes in tumorigenesis of MCC, especially in MCPyV-negative MCC combined with SCC.


Assuntos
Carcinoma de Célula de Merkel/genética , Carcinoma de Células Escamosas/genética , Histonas/genética , Neoplasias Cutâneas/genética , Idoso , Idoso de 80 Anos ou mais , Carcinogênese/genética , Carcinoma de Célula de Merkel/virologia , Carcinoma de Células Escamosas/virologia , Epigênese Genética/genética , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Poliomavírus das Células de Merkel/patogenicidade , Pessoa de Meia-Idade , Infecções por Polyomavirus/genética , Infecções por Polyomavirus/virologia , Neoplasias Cutâneas/virologia , Infecções Tumorais por Vírus/genética , Infecções Tumorais por Vírus/virologia
3.
Medicina (B Aires) ; 79(4): 265-270, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31487245

RESUMO

Malignant melanoma (MM) is the more aggressive form of skin cancer with a mortality rate in Argentina 1997-2001 = 1.1/100 000 in men and 0.6 in women. BRAF proto-oncogene is focus of intense research; its mutation is one of the main tumor promoters and occurs in approximately 50% of MM. Several drugs with clinical activity on BRAF mutations have been approved. The aim of the study is to evaluate the mutational status of BRAF (exon 15) in cutaneous MM biopsies and its relationship with histopathological characteristics. We carried out an observational, retrospective study of samples fixed in formaldehyde and paraffin embedded; reviewing age, sex, diagnosis, histopathological data, tumor size and percentage, viability for molecular analysis and melanin presence. We evaluated BRAF mutations with PCR/Sanger sequencing. For statistics we used Student's t test, Chi square, Wilcoxon and Fisher's exact test. We were able to purify and sequence 76% (38/49) samples, 13/38 (34%) from women and 25/38 (66%) from men, the median age being 70 years. Most frequent location: thorax 14/35 (40%). Histological type: Superficial spreading 18/38 (47%). Clark's levels, 11/38 (29%): I-II and 27/38 (71%): III, IV and V. Breslow's median: 1.6 mm. Radial growth phase 11/38 (29%) and 27/38 (71%) vertical. Presented mutations 16/38 (42%). As reported by other authors, no association was found between the mutational state of exon 15 and clinical or histopathological parameters.


Assuntos
Melanoma/genética , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Estudos Retrospectivos , Neoplasias Cutâneas/patologia
4.
Anticancer Res ; 39(8): 4085-4093, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366492

RESUMO

BACKGROUND/AIM: The identification of novel prognostic biomarkers for melanoma metastasis is essential to improve patient outcomes. To this aim, we characterized miRNA expression profiles in relation to metastasis in melanoma and correlated miRNAs expression with clinical-pathological factors. MATERIALS AND METHODS: MiR-145-5p, miR-150-5p, miR-182-5p, miR-203-3p, miR-205-5p and miR-211-5p expression levels were analyzed in primary cutaneous melanomas, including thin and thick melanomas, and in melanoma metastases by quantitative Real-Time PCR. RESULTS: A significantly lower miR-205-5p expression was found in metastases compared to primary melanomas. Furthermore, a progressive down-regulation of miR-205-5p expression was observed from loco-regional to distant metastasis. Significantly lower miR-145-5p and miR-203-3p expression levels were found in cases with Breslow thickness >1 mm, high Clark level, ulceration and mitotic rate ≥1/mm2 Conclusion: Our findings point to miR-205-5p as potential biomarker of distant metastases and to miR-145-5p and miR-203-3p as markers of aggressiveness in melanoma.


Assuntos
Melanoma/genética , MicroRNAs/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Neoplasias Cutâneas/patologia
5.
An Bras Dermatol ; 94(3): 287-292, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365656

RESUMO

BACKGROUND: Renal transplant recipients are submitted to immunosuppression to avoid graft rejection, which makes them susceptible to various conditions. Furthermore, these individuals present malignant tumors more frequently than the general population, including nonmelanoma skin cancer. The individual genetic basis that acts in the pathogenesis of cutaneous cancer may present a protection or susceptibility factor for disease development. One of these factors is the HLA complex. OBJECTIVE: To investigate HLA alleles association to the occurrence of nonmelanoma skin cancer in renal transplant recipients from São Paulo State. METHODS: A total of 213 patients (93 renal transplant recipients with nonmelanoma skin cancer and 120 renal transplant recipients without nonmelanoma skin cancer) were evaluated by retrospective and cross-sectional study. Epidemiological, clinical and HLA typing data were found in databases. HLA class I (A, B) and class II (DR) alleles were compared to establish their association with nonmelanoma skin cancer. RESULTS: Comparing renal transplant recipients with and without nonmelanoma skin cancer, the HLA-B*13 allele was associated with higher risk of developing nonmelanoma skin cancer while B*45 and B*50 alleles were associated with protection. STUDY LIMITATIONS: The HLA A, B and DR alleles identification for the kidney transplantation routine is done by low and medium resolution techniques that do not allow discrimination of specific alleles. CONCLUSION: The involvement of HLA alleles in nonmelanoma skin cancer in renal transplant recipients was confirmed in this study. Renal transplant recipients with HLA-B*13 showed higher risk for developing a skin cancer (OR= 7.29) and should be monitored for a long period of time after transplantation.


Assuntos
Antígenos HLA/genética , Transplante de Rim/efeitos adversos , Neoplasias Cutâneas/genética , Adulto , Idoso , Alelos , Brasil/epidemiologia , Estudos de Casos e Controles , Estudos Transversais , Feminino , Predisposição Genética para Doença/genética , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-DR/genética , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Neoplasias Cutâneas/epidemiologia , Neoplasias Cutâneas/etiologia , Transplantados
6.
Mol Biol (Mosk) ; 53(4): 648-653, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31397438

RESUMO

Acral melanoma is one of the most aggressive and fast-growing forms of cutaneous melanoma and is characterized by a predominant location on the palms and feet. Primary tumors, metastases, and normal tissue samples from five acral melanoma patients were examined by massive parallel sequencing, focusing on the coding regions of 4100 genes involved in the origin and progression of hereditary and oncology diseases. Somatic mutations were found in genes related to cell division, proliferation, and apoptosis (BRAF, NRAS, VAV1, GATA1, and GCM2); cell adhesion (CTNND2 and ITGB4); angiogenesis (VEGFA); and the regulation of energy metabolism (BCS1L). Comparisons of target DNA sequences between morphologically normal and primary tumor tissues and between normal and metastatic tissues identified the candidate genes responsible for rapid metastasis in acral melanoma.


Assuntos
Melanoma/genética , Melanoma/patologia , Mutação , Metástase Neoplásica/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Humanos , Análise de Sequência de DNA
7.
Mol Biol (Mosk) ; 53(4): 663-673, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31397440

RESUMO

Malignant cutaneous melanoma (CM) is an extremely aggressive cancer characterized by a high level of metastatic activity and unfavorable prognosis due to a high incidence of relapses, as well as resistance to standard chemotherapy. Cutaneous melanoma accounts for 80% of deaths from malignant skin tumors. Nucleolin/C23 and nucleophosmin/B23, which constitute altogether ~70% of the nucleolus volume, are promising targets for molecular therapy of melanoma. These proteins perform many important functions in the cell, so disruption of the NCL and/or NPM gene structure and abnormal expression of the C23 and B23 proteins they encode, can lead to unlimited cell proliferation and progression of a tumor. Therefore, investigation of the structure and expression of these genes is a topical problem, which is important for understanding the mechanisms of CM carcinogenesis and for the development of new therapeutic approaches. This paper describes new NCL and NPM polymorphisms, as well as the levels of C23 and B23 expression in normal tissues, CM and mucosal melanoma.


Assuntos
Melanoma/genética , Melanoma/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Nucléolo Celular/química , Nucléolo Celular/metabolismo , Proliferação de Células , Humanos , Melanoma/tratamento farmacológico , Terapia de Alvo Molecular , Proteínas Nucleares/biossíntese , Proteínas Nucleares/química , Fosfoproteínas/biossíntese , Fosfoproteínas/química , Polimorfismo Genético , Proteínas de Ligação a RNA/biossíntese , Proteínas de Ligação a RNA/química , Neoplasias Cutâneas/tratamento farmacológico
8.
J Cancer Res Clin Oncol ; 145(9): 2241-2250, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31342168

RESUMO

PURPOSE: The tripartite motif (TRIM)16 acts as a tumour suppressor in both squamous cell carcinoma (SCC) and melanoma. TRIM16 is known to be secreted by keratinocytes, but no studies have been reported yet to assess the relationship between TRIM16 keratinocyte expression and melanoma development. METHODS: To study the role of TRIM16 in skin cancer development, we developed a keratinocyte TRIM16-specific knockout mouse model, and used the classical two-stage skin carcinogenesis challenge method, to assess the loss of keratinocyte TRIM16 on both papilloma, SCC and melanoma development in the skin after topical carcinogen treatment. RESULTS: Heterozygous, but not homozygous, TRIM16 knockout mice exhibited an accelerated development of skin papillomas and melanomas, larger melanoma lesions and an increased potential for lymph node metastasis. CONCLUSION: This study provides the first evidence that keratinocyte loss of the putative melanoma tumour suppressor protein, TRIM16, enhances melanomagenesis. Our data also suggest that TRIM16 expression in keratinocytes is involved in cross talk between keratinocytes and melanocytes, and has a role in melanoma tumorigenesis.


Assuntos
Proteínas de Transporte/genética , Queratinócitos/metabolismo , Perda de Heterozigosidade/fisiologia , Linfonodos/metabolismo , Melanócitos/metabolismo , Melanoma/genética , Neoplasias Cutâneas/genética , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Proteínas de Transporte/metabolismo , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Células Cultivadas , Regulação Neoplásica da Expressão Gênica , Queratinócitos/patologia , Linfonodos/patologia , Metástase Linfática , Melanócitos/patologia , Melanoma/metabolismo , Melanoma/patologia , Camundongos , Camundongos Knockout , Pele/metabolismo , Pele/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia
9.
Nat Med ; 25(6): 929-935, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171876

RESUMO

Melanoma treatment has progressed in the past decade with the development and approval of immune checkpoint inhibitors targeting programmed death 1 (PD-1) or its ligand (PD-L1) and cytotoxic T lymphocyte-associated antigen 4, as well as small molecule inhibitors of BRAF and/or MEK for the subgroup of patients with BRAFV600 mutations1-9. BRAF/MEK-targeted therapies have effects on the tumor microenvironment that support their combination with PD-1/PD-L1 inhibitors10-20. This phase Ib study (ClinicalTrials.gov, number NCT01656642 ) evaluated the safety and anti-tumor activity of combining atezolizumab (anti-PD-L1) with vemurafenib (BRAF inhibitor), or cobimetinib (MEK inhibitor) + vemurafenib, in patients with BRAFV600-mutated metastatic melanoma. Triple combination therapy with atezolizumab + cobimetinib + vemurafenib, after a 28-d run-in period with cobimetinib + vemurafenib, had substantial but manageable toxicity. Exploratory biomarker data show that the cobimetinib + vemurafenib run-in was associated with an increase in proliferating CD4+ T-helper cells but not with an increase in T-regulatory cells, as observed in the vemurafenib-only run-in period. The confirmed objective response rate was 71.8% (95% confidence interval 55.1-85.0). The estimated median duration of response was 17.4 months (95% confidence interval 10.6-25.3) with ongoing response in 39.3% of patients after 29.9 months of follow-up. Further investigation in a phase III trial is underway.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Azetidinas/administração & dosagem , Antígeno B7-H1/antagonistas & inibidores , Estudos de Coortes , Humanos , Estimativa de Kaplan-Meier , MAP Quinase Quinase Quinases/antagonistas & inibidores , Melanoma/secundário , Mutação , Piperidinas/administração & dosagem , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Vemurafenib/administração & dosagem
10.
Nat Med ; 25(6): 941-946, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171878

RESUMO

Blocking programmed death 1 (PD-1) may enhance the durability of anti-tumor responses that are induced by the combined inhibition of BRAF and MEK1. Here we performed a randomized phase 2 trial ( NCT02130466 ), in which patients with treatment-naive BRAFV600E/K-mutant, advanced melanoma received the BRAF inhibitor dabrafenib and the MEK inhibitor trametinib together with the PD-1-blocking antibody pembrolizumab (triplet; n = 60) or placebo (doublet; n = 60). The primary end point of progression-free survival was numerically improved in the triplet group-16.0 months-compared with 10.3 months in the doublet group (hazard ratio, 0.66; P = 0.043); however, the trial did not reach the planned benefit for a statistically significant improvement. Median duration of response was 18.7 months (95% confidence interval, 10.1-22.1) and 12.5 months (95% confidence interval, 6.0-14.1); 59.8 and 27.8% of responses were estimated to have lasted for more than 18 months for triplet and doublet treatment, respectively. Grade 3-5 treatment-related adverse events occurred in 58.3 and 26.7% of patients treated with triplet and doublet therapies, respectively, which were most commonly fever, increased transaminase levels and rash. One patient who received triplet therapy died of pneumonitis. In summary, triplet therapy with dabrafenib, trametinib and pembrolizumab conferred numerically longer progression-free survival and duration of response with a higher rate of grade 3/4 adverse events compared with the doublet therapy of dabrafenib, trametinib and placebo.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Método Duplo-Cego , Feminino , Humanos , Imidazóis/administração & dosagem , Estimativa de Kaplan-Meier , MAP Quinase Quinase Quinases/antagonistas & inibidores , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Mutação , Oximas/administração & dosagem , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Neoplasias Cutâneas/patologia , Adulto Jovem
11.
Nat Med ; 25(6): 936-940, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171879

RESUMO

Oncogene-targeted therapy with B-Raf proto-oncogene (BRAF) and mitogen-activated protein kinase kinase (MEK) inhibitors induces a high initial response rate in patients with BRAFV600-mutated melanoma, with a median duration of response of approximately 1 year1-3. Immunotherapy with antibodies to programmed death 1 (PD-1) produces lower response rates but with long response duration. Preclinical models suggest that combining BRAF and MEK inhibitors with PD-1 blockade therapy improves antitumor activity4-6, which may provide additional treatment options for patients unlikely to have long-lasting responses to either mode of therapy alone. We enrolled 15 patients with BRAFV600-mutated metastatic melanoma in a first-in-human clinical trial of dabrafenib, trametinib and pembrolizumab ( NCT02130466 ). Eleven patients (73%) experienced grade 3/4 treatment-related adverse events, the most common being elevation of liver function tests and pyrexia, most of which resolved with drug interruption or discontinuation of either the anti-PD-1 antibody or the targeted therapy combination. Eleven patients (73%; 95% confidence interval = 45-92%) had an objective response, and six (40%; 95% confidence interval = 16-68%) continued with a response at a median follow-up of 27 months (range = 10.3-38.4+ months) for all patients. This study suggests that this triple-combined therapy may benefit a subset of patients with BRAFV600-mutated metastatic melanoma by increasing the frequency of long-lasting antitumor responses.


Assuntos
MAP Quinase Quinase Quinases/antagonistas & inibidores , Melanoma/tratamento farmacológico , Melanoma/genética , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Imidazóis/administração & dosagem , Imunoterapia , Masculino , Melanoma/secundário , Pessoa de Meia-Idade , Mutação , Oximas/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Neoplasias Cutâneas/terapia , Adulto Jovem
12.
Gene ; 711: 143941, 2019 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-31242453

RESUMO

Inorganic arsenic is a well-known carcinogen associated with several types of cancer, but the mechanisms involved in arsenic-induced carcinogenesis are not fully understood. Recent evidence points to epigenetic dysregulation as an important mechanism in this process; however, the effects of epigenetic alterations in gene expression have not been explored in depth. Using microarray data and applying a multivariate clustering analysis in a Gaussian mixture model, we describe the alterations in DNA methylation around the promoter region and the impact on gene expression in HaCaT cells during the transformation process caused by chronic exposure to arsenic. Using this clustering approach, the genes were grouped according to their methylation and expression status in the epigenetic landscape, and the changes that occurred during the cellular transformation were identified adequately. Thus, we present a valuable method for identifying epigenomic dysregulation.


Assuntos
Arsênico/toxicidade , Transformação Celular Neoplásica/patologia , Metilação de DNA/efeitos dos fármacos , Perfilação da Expressão Gênica/métodos , Neoplasias Cutâneas/patologia , Animais , Linhagem Celular Tumoral , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/genética , Epigênese Genética/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Transplante de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Regiões Promotoras Genéticas , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/genética
13.
Cancer Immunol Immunother ; 68(7): 1121-1132, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31134297

RESUMO

Immune-cell infiltration is associated with improved survival in melanoma. Human melanoma metastases may be grouped into immunotypes representing patterns of immune-cell infiltration: A (sparse), B (perivascular cuffing), and C (diffuse). Immunotypes have not been defined for murine melanomas, but may provide opportunities to understand mechanism-driving immunotype differences. We performed immunohistochemistry with immune-cell enumeration, immunotyping, and vascular density scoring in genetically engineered (Braf/Pten and Braf/Pten/ß-catenin) and transplantable (B16-F1, B16-OVA, and B16-AAD) murine melanomas. The transplantable tumors were grown in subcutaneous (s.c.) or intraperitoneal (i.p.) locations. Braf/Pten and Braf/Pten/ß-catenin tumors had low immune-cell densities, defining them as Immunotype A, as did B16-F1 tumors. B16-OVA (s.c. and i.p.) and B16-AAD s.c. tumors were Immunotype B, while B16-AAD i.p. tumors were primarily Immunotype C. Interestingly, the i.p. location was characterized by higher immune-cell counts in B16-OVA tumors, with counts that trended higher for B16-F1 and B16-AAD. The i.p. location was also characterized by higher vascularity in B16-F1 and B16-AAD tumors. These findings demonstrate that spontaneously mutated neoantigens in B16 melanomas were insufficient to induce robust intratumoral immune-cell infiltrates, but instead were Immunotype A tumors. The addition of model neoantigens (OVA or AAD) to B16 enhanced infiltration, but this most often resulted in Immunotype B. We find that tumor location may be an important element in enabling Immunotype C tumors. In aggregate, these data suggest important roles both for the antigen type and for the tumor location in defining immunotypes.


Assuntos
Antígenos de Neoplasias/imunologia , Imunofenotipagem , Melanoma Experimental/imunologia , Neoplasias Cutâneas/imunologia , Animais , Linhagem Celular Tumoral/transplante , Humanos , Melanoma Experimental/genética , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas B-raf/genética , Pele/patologia , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Análise Serial de Tecidos , beta Catenina/genética
14.
Int J Mol Sci ; 20(9)2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-31052530

RESUMO

Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans and it can be locally invasive and metastatic to distant sites. MicroRNAs (miRNAs or miRs) are endogenous, small, non-coding RNAs of 19-25 nucleotides in length, that are involved in regulating gene expression at a post-transcriptional level. MicroRNAs have been implicated in diverse biological functions and diseases. In cancer, miRNAs can proceed either as oncogenic miRNAs (onco-miRs) or as tumor suppressor miRNAs (oncosuppressor-miRs), depending on the pathway in which they are involved. Dysregulation of miRNA expression has been shown in most of the tumors evaluated. MiRNA dysregulation is known to be involved in the development of cutaneous squamous cell carcinoma (CSCC). In this review, we focus on the recent evidence about the role of miRNAs in the development of CSCC and in the prognosis of this form of skin cancer.


Assuntos
Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias Cutâneas/genética , Animais , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/patologia , Humanos , Prognóstico , Pele/metabolismo , Pele/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia
15.
Hautarzt ; 70(7): 490-496, 2019 Jul.
Artigo em Alemão | MEDLINE | ID: mdl-31143971

RESUMO

Skin tumors can manifest solitarily and sporadically but can also be multiple and familial. Beside the skin, hereditary cutaneous tumor syndromes also affect extracutaneous organs and are clinically and genetically heterogeneous. Taking the medical history, a clinical examination and dermatopathological characterization of the respective neoplasia will help the dermatologist to reach a diagnosis at an early stage. Subsequently, this diagnosis can be unambiguously confirmed by molecular genetic analysis. Here, we provide an overview and update on selected hereditary cutaneous tumor syndromes.


Assuntos
Testes Genéticos/métodos , Técnicas de Diagnóstico Molecular/métodos , Síndromes Neoplásicas Hereditárias/diagnóstico , Síndromes Neoplásicas Hereditárias/genética , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/genética , Predisposição Genética para Doença , Humanos , Biologia Molecular , Pele
16.
Oncology ; 97(1): 26-37, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31071716

RESUMO

OBJECTIVE: Normally, activation of tropomyosin-related kinase (TRK) receptors by neurotrophins (NTs) stimulates intracellular pathways involved in cell survival and proliferation. Dysregulation of NT/TRK signaling may affect neoplasm prognosis. Data on NT and TRK expression in melanomas are limited, and it is unclear whether NT/TRK signaling pathways are involved in the origin and progression of this neoplasm. METHODS: We examined whether NT/TRK expression differs across different cutaneous melanoma grades and subtypes, and whether it is associated with melanoma prognosis and survival. A cross-sectional study was performed in which the expression of TrkA, TrkB, nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) was analyzed by immunohistochemistry of 154 melanoma samples. We investigated NT/TRK expression associations with prognostic factors for melanoma, relapse-free survival (RFS), and overall survival (OS). RESULTS: Of the 154 melanoma samples, 77 (55.4%) were TrkA immunopositive, 81 (58.3%) were TrkB immunopositive, 113 (81.3%) were BDNF immunopositive, and 104 (75.4%) were NGF immunopositive. We found NT/TRK expression associated strongly with several clinical prognostic factors, including the tumor-node-metastasis stage (p < 0.001), histological subtype (p < 0.001), and Clark level (p < 0.05), as well as with a worse OS (p < 0.05 for all, except TrkB) and RFS (p < 0.05 for all). CONCLUSIONS: Our results show strong associations of NT/TRK expression with melanoma stage progression and a poor prognosis.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/genética , Melanoma/genética , Glicoproteínas de Membrana/genética , Fatores de Crescimento Neural/genética , Receptor trkA/genética , Receptor trkB/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Melanoma/imunologia , Melanoma/patologia , Glicoproteínas de Membrana/imunologia , Pessoa de Meia-Idade , Fator de Crescimento Neural/genética , Fatores de Crescimento Neural/imunologia , Prognóstico , Receptor trkA/imunologia , Receptor trkB/imunologia , Transdução de Sinais , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Adulto Jovem
17.
J Drugs Dermatol ; 18(5): 448-453, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31141850

RESUMO

Background: Studies have identified numerous genetic polymorphisms associated with increased risk of melanoma and non-melanoma skin cancer (NMSC). In this pilot study, we aimed to examine whether previously identified melanoma and non-melanoma associated single nucleotide polymorphisms (SNPs) which were found to be associated with cutaneous malignancy were also present in a relatively heterogeneous population with a history of skin cancer versus an age and environmental matched controls. The undertaking of this project serves to further the current understanding of the genetic profile for those at higher risk for developing skin cancer. Methods: Nineteen NMSC patients and their age-matched and environmental controls underwent genotyping of 7 previously discovered SNPs associated with melanoma and NMSC. Results: In a random, heterogeneous population in Southern California, SNP's Chr1, PAD16, PIGU, TDG had a similar association with NMSC previously reported in prior studies. Due to small trial size, no conclusions or observable associations could be drawn from the SNPs MC1R, TP53, and XRCC1. Conclusion: This data supports that 4 of the 7 SNP's studied had similar associations and could potentially be predictive tool of NMSC risk in this patient population. The remaining three SNP's did not have a definitive association with malignancy. Larger studies are needed to further elucidate the specific roles of these SNPs collectively and ultimately to develop a genetic profile for those patients at increased risk of developing skin cancer. J Drugs Dermatol. 2019;18(5):448-453.


Assuntos
Predisposição Genética para Doença , Melanoma/epidemiologia , Mucosa Bucal/patologia , Polimorfismo de Nucleotídeo Único/genética , Neoplasias Cutâneas/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , California/epidemiologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Melanoma/etiologia , Melanoma/genética , Pessoa de Meia-Idade , Projetos Piloto , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/genética , Manejo de Espécimes , Adulto Jovem
18.
Nat Commun ; 10(1): 2157, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089138

RESUMO

T cell senescence and exhaustion are major barriers to successful cancer immunotherapy. Here we show that miR-155 increases CD8+ T cell antitumor function by restraining T cell senescence and functional exhaustion through epigenetic silencing of drivers of terminal differentiation. miR-155 enhances Polycomb repressor complex 2 (PRC2) activity indirectly by promoting the expression of the PRC2-associated factor Phf19 through downregulation of the Akt inhibitor, Ship1. Phf19 orchestrates a transcriptional program extensively shared with miR-155 to restrain T cell senescence and sustain CD8+ T cell antitumor responses. These effects rely on Phf19 histone-binding capacity, which is critical for the recruitment of PRC2 to the target chromatin. These findings establish the miR-155-Phf19-PRC2 as a pivotal axis regulating CD8+ T cell differentiation, thereby paving new ways for potentiating cancer immunotherapy through epigenetic reprogramming of CD8+ T cell fate.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Melanoma Experimental/imunologia , MicroRNAs/metabolismo , Neoplasias Cutâneas/imunologia , Fatores de Transcrição/metabolismo , Transferência Adotiva/métodos , Animais , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/transplante , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Senescência Celular/genética , Senescência Celular/imunologia , Epigênese Genética/imunologia , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Melanoma Experimental/genética , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/genética , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/metabolismo , Complexo Repressor Polycomb 2/imunologia , Complexo Repressor Polycomb 2/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/terapia , Fatores de Transcrição/genética , Fatores de Transcrição/imunologia
19.
Neoplasma ; 66(4): 631-636, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31058533

RESUMO

Because of the conflicting conclusions on BRAF mutations in the natural course of non-metastatic melanoma their prognostic significance is still controversial. The present study aims to assess the prevalence and prognostic significance of BRAF V600E mutation and apprehend its association with clinicopathologic features in stage I to III Turkish melanoma patients. A total of 93 adult stages I to III cutaneous primary melanoma patients were included in the study. BRAF V600E mutation was detected using the Real Time PCR. Median age was 52 years (range, 18 to 84) and 68.8% of the patients were men. Overall, BRAF V600E mutation was detected in 46.2% (43/93) of the patients. In stages I and II, trunk was the most frequently affected localization (47.1%) (p=0.05) and regression was found more prevalent in BRAF-mutant patients (38.5%) (p=0.05). Furthermore, males were predominant among stage III BRAF-mutant patients (80.8%) (p=0.05), and both superficially spreading histology subtype (45.0%) (p=0.05) and lower mitotic rate (36.4%) (p=0.02) also were more commonly associated with stage III BRAF-mutant patients. A significantly favorable relapse free survival was found in stage III node-positive BRAF-mutant patients (p=0.02), on the other hand BRAF status was not found to be associated with relapse free survival in stage I and stage II patients (p=0.3). Moreover, there was no overall survival association between stages and BRAF status (p=0.1 and p=0.2). In conclusion, there is no prognostic value of BRAF V600E mutation on overall survival in stage I-III melanoma patients, yet its presence might indicate a decreased risk for development of relapse and/or metastasis in stage III melanoma patients.


Assuntos
Melanoma/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Estadiamento de Neoplasias , Prognóstico , Adulto Jovem
20.
Vet J ; 247: 71-74, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30971355

RESUMO

Cutaneous mast cell tumours (MCT) are among the most frequent malignancies in dogs. Their clinical behaviour is highly variable and, with the exception of mutations in the c-kit gene, little is known about their genetic aetiology. The mutational status of the c-kit exons 8, 9 and 11, and exons 5-8 of the TP53 gene was analysed to find markers for molecular stratification of MCTs and predictors of clinical outcome. Mutations in the c-kit gene were detected in 19.5% (n = 8/41) samples and their presence was significantly associated with the high histopathological grade (P = 0.038). Mutations in the DNA binding domain of the TP53 gene were found in 14.6% (n = 6/41) of the analysed MCTs, and their frequency was similar in low and high grade MCTs (P > 0.05). TP53 mutations were not useful prognostic factors in this sample of canine cutaneous MCTs.


Assuntos
Doenças do Cão/genética , Mastocitose Cutânea/veterinária , Mutação , Proteínas Proto-Oncogênicas c-kit/genética , Neoplasias Cutâneas/veterinária , Proteína Supressora de Tumor p53/genética , Animais , Doenças do Cão/patologia , Cães , Frequência do Gene , Mastocitose Cutânea/genética , Mastocitose Cutânea/patologia , Gradação de Tumores/veterinária , Prognóstico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia
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