RESUMO
VHL gene is often inactivated in sporadic clear cell renal cancer (CCRC) due to somatic mutations, and it's germline mutations cause hereditary CCRC--von Hippel-Lindau syndrome. Localization of mutations in VHL, identification of new mutations and their influence on CCRC progression and sensitivity to targeted therapy are actual problems in modern oncogenetics. We have provided search and characterization of mutations in 248 primary CCRC using SSCP-analysis and sequencing. Somatic mutations were detected in 37.5% of samples, 72% of mutations were identified for the first time. New missense-mutations were analyzed by alignment programs and three-dimensional structure modeling. Mutation frequency was compared in different groups of patients in respect to stage, grade, and metastases. It was demonstrated that 39.1% samples with stage I harbor somatic mutations, however, no association with progression or metastases was found. We also have investigated localization of mutations in the VHL coding part and positions of missense-mutations and inframe deletions/insertions focusing on VHL critical sequences. VHL mutation analysis performed in this study improve the possibilities of laboratory diagnostics of familial and sporadic CCRC.
Assuntos
Carcinoma de Células Renais/genética , Neoplasias Renais/genética , Mutação Puntual/genética , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Doença de von Hippel-Lindau/genética , Carcinoma de Células Renais/patologia , Progressão da Doença , Estudos de Associação Genética , Humanos , Neoplasias Renais/patologia , Metástase Neoplásica , Estadiamento de Neoplasias , Fases de Leitura Aberta/genética , Estrutura Terciária de Proteína , Análise de Sequência de DNA , Relação Estrutura-Atividade , Doença de von Hippel-Lindau/patologiaRESUMO
The multi-center non-randomized clinical study included 38 patients, aged 31-70, with morphologically (histologically and/or cytologically) verified diagnosis of disseminated cutaneous melanoma established objective response in 18.5% and clinically significant effect (55.5%) following first-line treatment with fotemustine in conjunction with cisplatin and tamoxifen. Fotemustine as a first-line component of combination chemotherapy retarded metastatic spread to the brain. Since side-effects incidence was not high, the regimen may be used under outpatient hospital conditions.
