Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma.
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Authors
Jafri, MariamWake, Naomi C
Ascher, David B
Pires, Douglas E V
Gentle, Dean
Morris, Mark R.
Rattenberry, Eleanor
Simpson, Michael A
Trembath, Richard C
Weber, Astrid
Woodward, Emma R
Donaldson, Alan
Blundell, Tom L
Latif, Farida
Maher, Eamonn R
Issue Date
2015-04-14
Metadata
Show full item recordAbstract
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.Citation
Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma. 2015, 5 (7):723-9 Cancer DiscovPublisher
American Association for Cancer ResearchJournal
Cancer discoveryPubMed ID
25873077Type
Journal articleLanguage
enISSN
2159-82902159-8274
ae974a485f413a2113503eed53cd6c53
10.1158/2159-8290.CD-14-1096
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