Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Dosagem de Genes , Melanoma , Proteínas de Neoplasias , Fosfoproteínas , Proteínas Serina-Treonina Quinases , Transdução de Sinais/genética , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Via de Sinalização Hippo , Humanos , Masculino , Melanoma/genética , Melanoma/metabolismo , Melanoma/mortalidade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Fosfoproteínas/biossíntese , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Taxa de Sobrevida , Fatores de Transcrição , Proteínas de Sinalização YAPRESUMO
BACKGROUND: The impact of BRAF tumor mutations on the natural course of disease of melanoma patients is controversial. PATIENTS AND METHODS: We analyzed the mutational status and overall survival of 215 patients receiving treatment with dacarbazine or temozolomide. All patients who started first-line treatment at our institution between 2000 and 2010 were included to prevent selection and bias due to thereafter arising therapeutic options. RESULTS: No patient received BRAF- or MEK-inhibitors during follow-up. Survival was associated with the pattern of visceral involvement, the presence of brain metastases and the serum lactate dehydrogenase level (all p<0.001). The BRAF-V600 mutational status was not associated with survival and no differences in overall survival were detected according to age, gender or to the cytotoxic agent used for therapy. In Cox regression analysis the presence of brain metastases (hazard ratio 2.3; p<0.001) and an elevated serum LDH (hazard ratio 2.5; p<0.001) were the only factors, which independently predicted survival. CONCLUSIONS: No differences in prognosis were observed according to the BRAF mutational status in patients with distant metastasis treated with monochemotherapy.
Assuntos
Neoplasias Encefálicas/genética , Dacarbazina/análogos & derivados , Dacarbazina/uso terapêutico , Melanoma/genética , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias Cutâneas/genética , Adulto , Idoso , Antineoplásicos Alquilantes/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Feminino , Seguimentos , Humanos , Masculino , Melanoma/tratamento farmacológico , Melanoma/mortalidade , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/secundário , Taxa de Sobrevida , TemozolomidaRESUMO
The prognostic impact of BRAF-V600 tumor mutations in stage I/II melanoma patients has not yet been analyzed in detail. We investigated primary tumors of 437 patients diagnosed between 1989 and 2006 by Sanger sequencing. Mutations were detected in 38.7% of patients and were associated with age, histological subtype as well as mitotic rate. The mutational rate was 36.7% in patients with disease-free course and 51.7% in those with subsequent distant metastasis (p = 0.031). No difference in overall survival (p = 0.119) but a trend for worse distant-metastasis-free survival (p = 0.061) was observed in BRAF mutant compared to BRAF wild-type patients. Independent prognostic factors for overall survival were tumor thickness, mitotic rate and ulceration. An interesting significant prognostic impact was observed in patients with tumor thickness of 1 mm or less, with the mutation present in 6 of 7 patients dying from melanoma. In conclusion, no significant survival differences were found according to BRAF-V600 tumor mutations in patients with primary melanoma but an increasing impact of the mutational status was observed in the subgroup of patients with tumor thickness of 1 mm or less. A potential role of the mutational status as a prognostic factor especially in this subgroup needs to be investigated in larger studies.
Assuntos
Melanoma/genética , Melanoma/mortalidade , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Idoso , Feminino , Humanos , Masculino , Melanoma/patologia , Melanoma/cirurgia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Sistema de Registros , Neoplasias Cutâneas , Melanoma Maligno CutâneoRESUMO
Several viruses are known to cause cancer, such as human herpes virus 8 in Kaposi sarcoma and human papilloma viruses in cervical cancer. Recently, Merkel cell polyoma virus (MCPyV) has been described in 80% of Merkel cell carcinomas (MCC). Similarly to MCC and Kaposi sarcoma, melanoma incidence is increased in immunosuppressed patients. We asked whether infection by known or yet unknown viruses may play a role in melanoma development as well. To detect viral sequences expressed in melanoma cells, we analysed three melanoma metastases by whole-transcriptome sequencing and digital transcriptome subtraction. None of the samples investigated harboured viral sequences. In contrast, artificial viral sequences and MCPyV transcripts used as a positive control for the bioinformatics analysis were detected. This renders it less likely that viruses are frequently involved in melanoma induction. A larger number of melanoma transcriptome sequencings are required to rule out viruses as a relevant pathogen.
Assuntos
Genoma Viral , Melanoma/secundário , Melanoma/virologia , Humanos , Melanoma/genética , Vírus Oncogênicos/genética , Vírus Oncogênicos/isolamento & purificação , TranscriptomaRESUMO
Recently, merkel cell polyoma virus (MCPyV) has been described in 80% of merkel cell carcinomas (MCC). Similar to MCC, melanoma incidence is increased in immuno-suppressed patients. We hypothesized that MCPyV may play a role in melanoma development as well. We selected 95 archival, paraffin-embedded primary melanomas. DNA was obtained from micro-dissected tissue and amplified with PCR primer sets specific for the MCPyV T-antigen locus (LT1 and LT3) and for the VP1 gene. None of the 95 melanoma samples did show LT1, LT3, or VP1 fragment amplification. In conclusion, there is no evidence that MCPyV infection plays a role in cutaneous melanoma development.
Assuntos
Melanoma/virologia , Polyomavirus/isolamento & purificação , Neoplasias Cutâneas/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos Virais de Tumores/genética , Proteínas do Capsídeo/genética , Carcinoma de Célula de Merkel/etiologia , Carcinoma de Célula de Merkel/virologia , DNA Viral/genética , DNA Viral/isolamento & purificação , Feminino , Humanos , Masculino , Melanoma/etiologia , Pessoa de Meia-Idade , Polyomavirus/genética , Polyomavirus/patogenicidade , Infecções por Polyomavirus/complicações , Neoplasias Cutâneas/etiologiaRESUMO
The heterodimeric integrins are important receptors for the attachment of cells to their extracellular matrix. Here, we studied the attachment of human mesenchymal stem cells (MSCs) to type I collagen (col-1), which is part of the extracellular matrix in bone, skin, and connective tissues. Furthermore, we examined how TGF-beta influences the integrin expression and attachment of MSC. Using flow cytometry, immunoblot, and RT-PCR, we report that MSC express several integrin subunits, including the alpha(2)beta(1) integrin (VLA-2, CD49b/CD29). TGF-beta increases the expression of integrin subunits alpha(2), alpha(6), and beta(1) in MSC, thereby enhancing the attachment of MSC to col-1. The TGF-beta-mediated up-regulation of the expression of the integrin subunits alpha(2) and alpha(6) is mainly mediated in MSC by Smad2.