RESUMEN
BACKGROUND: Mucosal melanomas in the head and neck region are most frequently located in the nasal cavity and paranasal sinuses. Sinonasal mucosal melanoma (SNMM) comprises <1% of all melanomas. The aim was to determine the KIT, NRAS and BRAF mutation frequencies in a large series of primary SNMMs. METHODS: Laser capture microdissection was used to isolate tumour cells from 56 formalin-fixed paraffin-embedded tumours. The tumour cells were screened for KIT, NRAS and BRAF mutations by direct sequencing. RESULTS: Overall, 21% (12 out of 56) of SNMMs harboured KIT, NRAS or BRAF mutations. Mutations in these oncogenes occurred in a mutually exclusive manner. Both KIT and BRAF mutations were identified at a similar frequency of 4% each (2 out of 56), whereas NRAS mutations were detected in 14% (8 out of 56) of the SNMMs. Four of the NRAS mutations were located in exon 1. Mutations in these oncogenes were significantly more common in melanomas located in the paranasal sinuses than in nasal cavity (P=0.045). In a multivariate analysis, patients with melanomas in the nasal cavity had a significantly better overall survival than those with tumours in the paranasal sinuses (P=0.027). CONCLUSION: Our findings show that KIT and BRAF mutations, which are accessible for present targeted therapies, are only rarely present in SNMMs, whereas NRAS mutations seem to be relatively more frequent. The data show that majority of SNMMs harbour alterations in genes other than KIT, NRAS and BRAF.
Asunto(s)
GTP Fosfohidrolasas/genética , Melanoma/genética , Proteínas de la Membrana/genética , Mutación , Neoplasias de los Senos Paranasales/genética , Proteínas Proto-Oncogénicas B-raf/genética , Proteínas Proto-Oncogénicas c-kit/genética , Anciano , Anciano de 80 o más Años , Análisis Mutacional de ADN , Femenino , Humanos , Captura por Microdisección con Láser , Masculino , Melanoma/patología , Persona de Mediana Edad , Adhesión en Parafina , Tasa de SupervivenciaRESUMEN
Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by dryness of the eyes and mouth. Currently, the highly polymorphic major histocompatibility complex (MHC) genes are the best documented genetic risk factor for the development of autoimmune disease. We examined the MHC class II alleles DRB1, DRB3, DRB4, DRB5, DQA1 and DQB1 in a group of Norwegian pSS patients and compared with a group of healthy controls. Because a number of studies have shown that some of the MHC class II alleles are not associated with the disease as a whole, but rather to the development of autoantibodies, anti-Ro52 autoantibodies in serum were measured and compared to MHC class II allele status. A clear association with pSS was detected for the DRB1*0301 and DRB3*0101 alleles, but these alleles were more closely associated with the presence of anti-Ro52 autoantibodies than with pSS itself. Moreover, the DQA1*0501 and DQB1*0201 alleles were only associated with the presence of anti-Ro52 autoantibodies. This study shows that the production of anti-Ro52 autoantibodies in pSS is associated with the DRB1*0301, DRB3*0101, DQA1*0501 and DQB1*0201 alleles which are in strong linkage disequilibrium.
Asunto(s)
Alelos , Autoanticuerpos/sangre , Autoantígenos/inmunología , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , ARN Citoplasmático Pequeño , Ribonucleoproteínas/inmunología , Síndrome de Sjögren/inmunología , Femenino , Antígenos HLA-DQ/inmunología , Cadenas alfa de HLA-DQ , Cadenas beta de HLA-DQ , Antígenos HLA-DR/inmunología , Cadenas HLA-DRB1 , Cadenas HLA-DRB3 , Cadenas HLA-DRB4 , Cadenas HLA-DRB5 , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Inmunoglobulina A/sangre , Inmunoglobulina A/inmunología , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Isotipos de Inmunoglobulinas/sangre , Isotipos de Inmunoglobulinas/inmunología , Inmunoglobulina M/sangre , Inmunoglobulina M/inmunología , Masculino , Noruega , Síndrome de Sjögren/sangre , Síndrome de Sjögren/genética , Antígeno SS-BRESUMEN
Beta-catenin plays an important role in the Wnt signaling pathway by activating T-cell factor (Tcf)/lymphoid enhancer factor (Lef)-regulated gene transcription. The level of beta-catenin is regulated through GSK-3beta phosphorylation of specific serine and threonine residues, all of which are encoded for in exon 3 of the beta-catenin gene (CTNNB1). Mutations altering the GSK-3beta phosphorylation sites lead to cellular accumulation of beta-catenin and constitutive transcription of Tcf/Lef target genes. Such mutations have previously been found in melanoma cell lines. In our study, primary melanomas and their corresponding metastases were screened for CTNNB1 exon 3 mutations using single-strand conformation polymorphism and nucleotide sequence analysis. One of 31 primary tumors and 1 of 37 metastases, both originating from the same patient, had a TCT to TTT mutation at codon 45, changing serine to phenylalanine. Immunohistochemical analysis revealed membranous localization of beta-catenin in a majority of the samples. The mutated primary tumor and metastasis, however, displayed widespread cytoplasmic and nuclear expression of beta-catenin. An additional 30% of the primary tumors showed focal cytoplasmic and nuclear staining. Thus, beta-catenin exon 3 mutations are rare in primary as well as metastatic melanomas and do not explain the abnormal cytoplasmic and nuclear localization of beta-catenin found in a relatively large fraction of primary melanomas.