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

Familial renal cell carcinoma (RCC) is genetically heterogeneous and may be causedby mutations in multiple genes, including VHL , MET , SDHB , FH , FLCN , PTEN , andBAP1 . However, most individuals with inherited RCC do not have a detectable germline mutation. Toidentify novel inherited RCC genes, we undertook exome resequencing studies in a familial RCC kindredand identifi ed 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 candidateCDKN2B missense mutations (p.Pro40Thr, p.Ala23Glu, and p.Asp86Asn). In silico analysis of the threedimensional structures indicated that each missense substitution was likely pathogenic through reducedstability of the mutant or reduced affi nity for cyclin-dependent kinases 4 and 6, and in vitro studiesdemonstrated that each of the mutations impaired CDKN2B-induced suppression of proliferation in anRCC cell line. These fi ndings identify germline CDKN2B mutations as a novel cause of familial RCC. SIGNIFICANCE: Germline loss-of-function CDKN2B mutations were identifi ed in a subset of patientswith features of inherited RCC. Detection of germline CDKN2B mutations will have an impact on familial cancer screening and might prove to infl uence the management of disseminated disease.