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

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Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma Published OnlineFirst April 14, 2015; DOI: 10.1158/2159-8290.CD-14-1096 RESEARCH BRIEF Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma Mariam Jafri 1,2 , Naomi C. Wake 1 , David B. Ascher 3 , Douglas E.V. Pires 3 , Dean Gentle 1 , Mark R. Morris 1,4 , Eleanor Rattenberry 1,5 , Michael A. Simpson 6 , Richard C. Trembath 6,7 , Astrid Weber8 , Emma R. Woodward 1,5 , Alan Donaldson 9 , Tom L. Blundell 3 , Farida Latif 1 , and Eamonn R. Maher 1,10 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 identifi ed a CDKN2B nonsense mutation that segregated with familial RCC status. Targeted rese- quencing 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 affi nity 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 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 patients with features of inherited RCC. Detection of germline CDKN2B mutations will have an impact on famil- ial cancer screening and might prove to infl uence the management of disseminated disease. Cancer Discov; 5(7); 723–9. ©2015 AACR. INTRODUCTION thermore, improved understanding of the molecular factors involved in tumorigenesis has provided a basis for the rational The identifi cation of the genetic basis for familial cancer development of targeted therapies. This is exemplifi ed in syndromes can provide important insights into the molecular inherited renal cell carcinoma (RCC; MIM#144700) in which mechanisms of familial and sporadic tumorigenesis. Fur- the identifi cation of mutations in the VHL tumor suppressor 1 Medical and Molecular Genetics, School of Clinical and Experimental Kingdom. 9 Department of Clinical Genetics, University Hospital Bristol Medicine, College of Medical and Dental Sciences, University of Birming- NHS Trust, St. Michael’s Hospital, Bristol, United Kingdom. 10 Department ham, Birmingham, United Kingdom. 2 Department of Oncology, University of Medical Genetics, University of Cambridge and NIHR Cambridge Bio- Hospital Birmingham Foundation Trust, Birmingham, United Kingdom. medical Research Centre, Cambridge, United Kingdom. 3 Department of Biochemistry, University of Cambridge, Cambridge, United Current address for D.E.V. Pires: Centro de Pesquisas René Rachou, 4 Kingdom. School of Applied Sciences, University of Wolverhampton, Wol- Fundação Oswaldo Cruz, Belo Horizonte, Brazil. verhampton, United Kingdom. 5 West Midlands Region Genetics Service, Birmingham Women’s Hospital, Birmingham, United Kingdom. 6 Division of Corresponding Author: Eamonn R. Maher, University of Cambridge, Box 238, Genetics and Molecular Medicine, King’s College London School of Medi- Cambridge Biomedical Campus, Cambridge CB2 2QQ, UK. Phone: 01223- cine, Guy’s Hospital, London, United Kingdom. 7 Queen Mary University of 746715; Fax: 01223-746777; E-mail: [email protected] London, Barts and The London School of Medicine and Dentistry, London, doi: 10.1158/2159-8290.CD-14-1096 8 United Kingdom. Royal Liverpool Children’s Hospital, Liverpool, United © 2015 American Association for Cancer Research. JULY 2015CANCER DISCOVERY | 723 Downloaded from cancerdiscovery.aacrjournals.org on September 28, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst April 14, 2015; DOI: 10.1158/2159-8290.CD-14-1096 RESEARCH BRIEF Jafri et al. A B RCC age 60 RCC RCC RCC age 60 age 57 age 56 Mutation c.103G>T(p.E35X) Corresponding normal sequence C Homo sapiens Callithrix jacchus Otolemur gametti Bos Taurus Felis catus Mus muscularis Rattus norvegicus Myotis lucifugus Tetraodon tropicalis Xenopus tropicalis c.68C>A p.Ala23Glu (A23E) Corresponding normal sequence D Homo sapiens Callithrix jacchus Otolemur gametti Bos Taurus Felis catus Mus muscularis Rattus norvegicus Myotis lucifugus Tetraodon tropicalis Xenopus tropicalis c.118C>A p.Pro40Thr (P40T) Corresponding normal sequence E Homo sapiens Callithrix jacchus Otolemur gametti Bos Taurus Mus muscularis Rattus norvegicus Myotis lucifugus Tetraodon tropicalis Xenopus tropicalis c.256G>A p.Asp86Asn (D86N) Corresponding normal sequence Figure 1. A, family pedigree for familial RCC kindred in which exome sequencing was performed . B, electropherogram showing heterozygous nonsense mutation (c.103G>T). C, electropherogram showing heterozygous missense mutation c.68C>A p.Ala23Glu (A23E) and evolutionary conservation of residue; D, electropherogram showing heterozygous missense mutation c. 118C>A p.Pro40Thr (P40T) and evolutionary conservation of residue; E, electrophero- gram showing heterozygous missense mutation. c.256G>A p.Asp86Asn (D86N) and evolutionary conservation of residue. gene (TSG) as the cause of von Hippel–Lindau (VHL) disease RESULTS (MIM#193300) led to the recognition that the VHL TSG is Identifi cation of CDKN2B Mutations somatically inactivated in the majority of sporadic clear-cell in Inherited RCC RCC. Subsequently, elucidation of the role of the VHL gene product in the regulation of hypoxia response pathways ena- Analysis of exome resequencing in a male proband diag- bled the development of novel targeted treatments that have nosed with familial clear-cell RCC (see Fig. 1A ) at age 57 years revolutionized the clinical management of RCC ( 1 ). revealed no candidate mutations in RCC predisposition genes About 3% of all cases of RCC occur in individuals with ( VHL , SDHB , FLCN , FH , PTEN , or BAP1 ). Further bioinformatic familial RCC ( 2 ). A number of genetic mechanisms have analysis was undertaken for the presence of pathogenic muta- been implicated in RCC predisposition. Thus, genome-wide tions in genes linked to cancer. A candidate nonsense mutation association studies have identifi ed several common genetic in CDKN2B was highlighted for further investigation, and the variants that predispose to RCC, and at least two loci are CDKN2B c.103G>T (p.Glu35Stop) mutation was confi rmed by linked to pVHL-regulated hypoxic gene response pathways [at Sanger sequencing (see Fig. 1B ). Two of his eight siblings had 2p21 (rs11894252) and 11q13.3 (rs7105934) close to EPAS1 been diagnosed with clear-cell RCC (two brothers diagnosed ( HIF2A) and CCND1 (Cyclin D1), respectively; ref. 3 ]. In famil- at ages 56 and 60 years, respectively), and his mother had been ial RCC, in addition to VHL , germline mutations in MET , diagnosed with RCC at age 60 years. DNA was available from FLCN , FH , SDHB , PTEN , and BAP1 have all been associated four living relatives, and family genotyping studies demon- with inherited RCC [ 2 (and references within), 4–6 ]. Consti- strated the c.103G>T CDKN2B nonsense mutation was present tutional translocations, particularly involving chromosome in the only living sibling affected by RCC, but not in three 3, can also cause inherited RCC ( 7 ). However, overall less than unaffected siblings ( Fig. 1A ). The c.103G>T CDKN2B nonsense 20% of patients with features of nonsyndromic inherited RCC mutation was not previously reported in publicly available large have a detectable mutation in a known familial RCC gene ( 2 , exome/genome sequencing sets comprising >13,000 CDKN2B 4–6 , 8, 9 ). To identify novel inherited RCC genes, we under- alleles (0/1,092 sample chromosomes in 1,000 genomes; ref. 10 ; took exome sequencing and targeted resequencing studies in and 0 of >6,000 samples in the NHLBI Exome Variant Server; individuals with features of inherited RCC and no detectable ref. 11 ). In addition, no other CDKN2B truncating mutations mutation in known RCC predisposition genes. were reported in the latter set of >12,000 CDKN2B alleles. 724 | CANCER DISCOVERYJULY 2015 www.aacrjournals.org Downloaded from cancerdiscovery.aacrjournals.org on September 28, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst April 14, 2015; DOI: 10.1158/2159-8290.CD-14-1096 CDKN2B Tumor Suppressor Gene and Renal Cell Carcinoma RESEARCH BRIEF A A23 D86 P40 BC D A: I19 A: A17 B: L65 A: R31 B: H68 A: K29 B: R89 B: P40 B: A19 B: D86 B: A23 B: D39 Figure 2. Structural analysis of the interaction network of variant residues in CDKN2B (for the wild-type CDKN2B–CDK6). Ionic interactions and hydrogen bonds are depicted as yellow dashes, hydrophobic interactions are presented in green, and weak polar interactions are presented in orange. A, overview: atoms from CDKN2B and CDK6 are shown in light green and dark gray, respectively; (B) p.Pro40, (C) p.Ala23, and (D) p.Asp86. CDK, cyclin-dependent kinase. To further investigate the potential role of CDKN2B mutations ent kinases (CDK) 4 or 6. The overall structure of CDKN2B in inherited renal cancer, mutation screening was performed in is very similar to CDKN2D and is expected to bind through 50 individuals with features of nonsyndromic inherited RCC its concave face to the cleft between the N- and C-terminal [either familial RCC (n = 37) or multiple RCC aged <50 years domains of CDK4 and CDK6. Binding of CDKN2B prevents ( n = 13)], and three candidate missense mutations were detected productive binding of ATP to the CDKs, and potentially ( Fig. 1C–E ). A rare sequence variant (c.256G>A) predicted to inhibiting movement of the PLSTIRE helix to its active con- cause a pathogenic missense substitution, p.Asp86Asn, was formation ( 14 ). detected in a proband who was diagnosed with clear-cell RCC The three variants identifi ed were spread across the protein at age 35 years. No other family members (her mother had ( Fig.
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