title: Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma.
abstract: Familial renal cell carcinoma (RCC) is genetically heterogeneous and may be caused by mutations in multiple genes, including VHL, MET, SDHB, FH, FLCN, PTEN, and BAP1. However, most individuals with inherited RCC do not have a detectable germline mutation. To identify novel inherited RCC genes, we undertook exome resequencing studies in a familial RCC kindred and identified a CDKN2B nonsense mutation that segregated with familial RCC status. Targeted resequencing of CDKN2B in individuals (n = 82) with features of inherited RCC then revealed three candidate CDKN2B missense mutations (p.Pro40Thr, p.Ala23Glu, and p.Asp86Asn). In silico analysis of the three-dimensional structures indicated that each missense substitution was likely pathogenic through reduced stability of the mutant or reduced affinity for cyclin-dependent kinases 4 and 6, and in vitro studies demonstrated that each of the mutations impaired CDKN2B-induced suppression of proliferation in an RCC cell line. These findings identify germline CDKN2B mutations as a novel cause of familial RCC.
  
  
  CONCLUSIONS
  Germline loss-of-function CDKN2B mutations were identified in a subset of patients with features of inherited RCC. Detection of germline CDKN2B mutations will have an impact on familial cancer screening and might prove to influence the management of disseminated disease.
authors: Medical and Molecular Genetics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom. Department of Oncology, University Hospital Birmingham Foundation Trust, Birmingham, United Kingdom.
authors: Mariam
authors: M
authors: Jafri
authors: Medical and Molecular Genetics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors: Naomi C
authors: NC
authors: Wake
authors: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors: David B
authors: DB
authors: Ascher
authors: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors: Douglas E V
authors: DE
authors: Pires
authors: Medical and Molecular Genetics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors: Dean
authors: D
authors: Gentle
authors: Medical and Molecular Genetics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom. School of Applied Sciences, University of Wolverhampton, Wolverhampton, United Kingdom.
authors: Mark R
authors: MR
authors: Morris
authors: Medical and Molecular Genetics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom. West Midlands Region Genetics Service, Birmingham Women's Hospital, Birmingham, United Kingdom.
authors: Eleanor
authors: E
authors: Rattenberry
authors: Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, United Kingdom.
authors: Michael A
authors: MA
authors: Simpson
authors: Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, United Kingdom. Queen Mary University of London, Barts and The London School of Medicine and Dentistry, London, United Kingdom.
authors: Richard C
authors: RC
authors: Trembath
authors: Royal Liverpool Children's Hospital, Liverpool, United Kingdom.
authors: Astrid
authors: A
authors: Weber
authors: Medical and Molecular Genetics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom. West Midlands Region Genetics Service, Birmingham Women's Hospital, Birmingham, United Kingdom.
authors: Emma R
authors: ER
authors: Woodward
authors: Department of Clinical Genetics, University Hospital Bristol NHS Trust, St. Michael's Hospital, Bristol, United Kingdom.
authors: Alan
authors: A
authors: Donaldson
authors: Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
authors: Tom L
authors: TL
authors: Blundell
authors: Medical and Molecular Genetics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
authors: Farida
authors: F
authors: Latif
authors: Medical and Molecular Genetics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom. Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, United Kingdom. erm1000@medschl.cam.ac.uk.
authors: Eamonn R
authors: ER
authors: Maher
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics*; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D007680:Kidney Neoplasms / Q000737:chemistry / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods*
chemical_list: C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6