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Cancer Discov. 2015 Jul;5(7):723-9. doi: 10.1158/2159-8290.CD-14-1096. Epub 2015 Apr 14.

Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma.

Author information

1
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.
2
Medical and Molecular Genetics, School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
3
Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom.
4
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.
5
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.
6
Division of Genetics and Molecular Medicine, King's College London School of Medicine, Guy's Hospital, London, United Kingdom.
7
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.
8
Royal Liverpool Children's Hospital, Liverpool, United Kingdom.
9
Department of Clinical Genetics, University Hospital Bristol NHS Trust, St. Michael's Hospital, Bristol, United Kingdom.
10
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.

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.

SIGNIFICANCE:

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.

PMID:
25873077
DOI:
10.1158/2159-8290.CD-14-1096
[Indexed for MEDLINE]
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