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dc.contributor.authorJafri, Mariam
dc.contributor.authorWake, Naomi C
dc.contributor.authorAscher, David B
dc.contributor.authorPires, Douglas E V
dc.contributor.authorGentle, Dean
dc.contributor.authorMorris, Mark R.
dc.contributor.authorRattenberry, Eleanor
dc.contributor.authorSimpson, Michael A
dc.contributor.authorTrembath, Richard C
dc.contributor.authorWeber, Astrid
dc.contributor.authorWoodward, Emma R
dc.contributor.authorDonaldson, Alan
dc.contributor.authorBlundell, Tom L
dc.contributor.authorLatif, Farida
dc.contributor.authorMaher, Eamonn R
dc.date.accessioned2016-10-18T09:42:18Z
dc.date.available2016-10-18T09:42:18Z
dc.date.issued2015-04-14
dc.identifier.citationGermline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma. 2015, 5 (7):723-9 Cancer Discov
dc.identifier.issn2159-8290
dc.identifier.issn2159-8274
dc.identifier.pmid25873077
dc.identifier.doi10.1158/2159-8290.CD-14-1096
dc.identifier.urihttp://hdl.handle.net/2436/620219
dc.description.abstractFamilial 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.
dc.languageENG
dc.language.isoen
dc.publisherAmerican Association for Cancer Research
dc.subject.meshCarcinoma, Renal Cell
dc.subject.meshCyclin-Dependent Kinase 4
dc.subject.meshCyclin-Dependent Kinase 6
dc.subject.meshCyclin-Dependent Kinase Inhibitor p15
dc.subject.meshFemale
dc.subject.meshGenetic Predisposition to Disease
dc.subject.meshGerm-Line Mutation
dc.subject.meshHumans
dc.subject.meshKidney Neoplasms
dc.subject.meshMale
dc.subject.meshMiddle Aged
dc.subject.meshModels, Molecular
dc.subject.meshMutation, Missense
dc.subject.meshPedigree
dc.subject.meshSequence Analysis, DNA
dc.titleGermline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma.
dc.typeJournal article
dc.identifier.journalCancer discovery
dc.date.accepted2015-04-09
html.description.abstractFamilial 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.


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