RESUMO
BACKGROUND: The von Hippel-Lindau (VHL) disease is a hereditary tumour syndrome caused by germline mutations in VHL tumour suppressor gene. The identification of VHL variants requires accurate classification which has an impact on patient management and genetic counselling. METHODS: The TENGEN (French oncogenetics network of neuroendocrine tumors) and PREDIR (French National Cancer Institute network for Inherited predispositions to kidney cancer) networks have collected VHL genetic variants and clinical characteristics of all VHL-suspected patients analysed from 2003 to 2021 by one of the nine laboratories performing VHL genetic testing in France. Identified variants were registered in a locus-specific database, the Universal Mutation Database-VHL database (http://www.umd.be/VHL/). RESULTS: Here we report the expert classification of 164 variants, including all missense variants (n=124), all difficult interpretation variants (n=40) and their associated phenotypes. After initial American College of Medical Genetics classification, first-round classification was performed by the VHL expert group followed by a second round for discordant and ambiguous cases. Overall, the VHL experts modified the classification of 87 variants including 30 variants of uncertain significance that were as (likely)pathogenic variants for 19, and as likely benign for 11. CONCLUSION: Consequently, this work has allowed the diagnosis and influenced the genetic counselling of 45 VHL-suspected families and can benefit to the worldwide VHL community, through this review.
Assuntos
Neoplasias Renais , Doença de von Hippel-Lindau , Humanos , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Testes Genéticos , Predisposição Genética para Doença , Doença de von Hippel-Lindau/genética , Doença de von Hippel-Lindau/patologia , Estudos de Associação Genética , Neoplasias Renais/genética , Mutação em Linhagem GerminativaRESUMO
Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor-2 (VEGFR-2), two protein tyrosine kinases, are involved in pathological disorders and the progression of different types of carcinomas. Concomitant inhibition of both tyrosine kinase activities appears to be an attractive target for cancer chemotherapy. A series of new quinazoline derivatives substituted by amide, urea, or carbamic acid ester groups have been synthesized. The biological activities of these new compounds have been evaluated for their enzyme inhibition and antiproliferative activities.
Assuntos
Antineoplásicos , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Neoplasias da Próstata/tratamento farmacológico , Inibidores de Proteínas Quinases , Quinazolinas , Ureia/química , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Carbamatos/química , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Masculino , Neoplasias da Próstata/enzimologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/síntese química , Quinazolinas/química , Quinazolinas/farmacologiaRESUMO
Overexpression of Aurora-A kinase is commonly detected in many cancers, whereas the von Hippel-Lindau protein (pVHL) is frequently mutated or absent in renal cell carcinoma and is involved in the Ub proteasome complex, an important degradation pathway. In order to establish a link between Aurora-A overexpression and lack of pVHL protein, we hypothesized that pVHL regulates Aurora-A expression through a physical interaction. We present the first evidence, from both biological assays and computational biology techniques, that human pVHL binds strongly to Aurora-A kinase. Extensive molecular modeling, docking, and dynamic simulations demonstrate that the structure of the pVHL protein would allow it to bind to the TPX2 binding region of Aurora-A. In view of Aurora-A's importance as a therapeutic target for the treatment of cancer, this observation provides novel insights into the Aurora-A/pVHL pathway. In addition, the detailed Aurora-A/pVHL binding structure obtained will be valuable for the design of future Aurora-A inhibitors as therapeutic agents.