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

2.50
Hdl Handle:
http://hdl.handle.net/2436/620219
Title:
Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma.
Authors:
Jafri, Mariam; Wake, 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
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.
Citation:
Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma. 2015, 5 (7):723-9 Cancer Discov
Publisher:
American Association for Cancer Research
Journal:
Cancer discovery
Issue Date:
Jul-2015
URI:
http://hdl.handle.net/2436/620219
DOI:
10.1158/2159-8290.CD-14-1096
PubMed ID:
25873077
Type:
Article
Language:
en
ISSN:
2159-8290; 2159-8274
Appears in Collections:
Cancer Research Group

Full metadata record

DC FieldValue Language
dc.contributor.authorJafri, Mariamen
dc.contributor.authorWake, Naomi Cen
dc.contributor.authorAscher, David Ben
dc.contributor.authorPires, Douglas E Ven
dc.contributor.authorGentle, Deanen
dc.contributor.authorMorris, Mark Ren
dc.contributor.authorRattenberry, Eleanoren
dc.contributor.authorSimpson, Michael Aen
dc.contributor.authorTrembath, Richard Cen
dc.contributor.authorWeber, Astriden
dc.contributor.authorWoodward, Emma Ren
dc.contributor.authorDonaldson, Alanen
dc.contributor.authorBlundell, Tom Len
dc.contributor.authorLatif, Faridaen
dc.contributor.authorMaher, Eamonn Ren
dc.date.accessioned2016-10-18T09:42:18Z-
dc.date.available2016-10-18T09:42:18Z-
dc.date.issued2015-07-
dc.identifier.citationGermline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma. 2015, 5 (7):723-9 Cancer Discoven
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.en
dc.languageENG-
dc.language.isoenen
dc.publisherAmerican Association for Cancer Researchen
dc.rightsArchived with thanks to Cancer discoveryen
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.en
dc.typeArticleen
dc.identifier.journalCancer discoveryen

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