title: An integrated computational approach can classify VHL missense mutations according to risk of clear cell renal carcinoma.
abstract: Mutations in the von Hippel-Lindau (VHL) gene are pathogenic in VHL disease, congenital polycythaemia and clear cell renal carcinoma (ccRCC). pVHL forms a ternary complex with elongin C and elongin B, critical for pVHL stability and function, which interacts with Cullin-2 and RING-box protein 1 to target hypoxia-inducible factor for polyubiquitination and proteasomal degradation. We describe a comprehensive database of missense VHL mutations linked to experimental and clinical data. We use predictions from in silico tools to link the functional effects of missense VHL mutations to phenotype. The risk of ccRCC in VHL disease is linked to the degree of destabilization resulting from missense mutations. An optimized binary classification system (symphony), which integrates predictions from five in silico methods, can predict the risk of ccRCC associated with VHL missense mutations with high sensitivity and specificity. We use symphony to generate predictions for risk of ccRCC for all possible VHL missense mutations and present these predictions, in association with clinical and experimental data, in a publically available, searchable web server.
authors: Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK lucy.gossage@doctors.org.uk lucy.gossage@cruk.cam.ac.uk.
authors: Lucy
authors: L
authors: Gossage
authors: Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK.
authors: Douglas E V
authors: DE
authors: Pires
authors: Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK, Centre for Biochemical Engineering and Biotechnology, University of Chile, Beauchef 850, Santiago, Chile.
authors: Álvaro
authors: Á
authors: Olivera-Nappa
authors: Centre for Biochemical Engineering and Biotechnology, University of Chile, Beauchef 850, Santiago, Chile.
authors: Juan
authors: J
authors: Asenjo
authors: MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Research Centre, Cambridge CB2 0QH, UK and.
authors: Mark
authors: M
authors: Bycroft
authors: Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK.
authors: Tom L
authors: TL
authors: Blundell
authors: Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Box 193 (R4) Addenbrooke's Hospital, Cambridge Biomedical Campus, Hill's Road, Cambridge CB2 0QQ, UK.
authors: Tim
authors: T
authors: Eisen
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics*; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D020125:Mutation, Missense; D010641:Phenotype; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics*; D006623:von Hippel-Lindau Disease / Q000235:genetics
chemical_list: D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human