title: Targeted exome sequencing in clear cell renal cell carcinoma tumors suggests aberrant chromatin regulation as a crucial step in ccRCC development.
abstract: Clear cell renal cell carcinomas are characterized by 3p loss, and by inactivation of Von Hippel Lindau (VHL), a tumorsuppressor gene located at 3p25. Recently, SETD2, located at 3p21, was identified as a new candidate ccRCC tumor-suppressor gene. The combined mutational frequency in ccRCC tumors of VHL and SETD2 suggests that there are still undiscovered tumor-suppressor genes on 3p. We screened all genes on 3p for mutations in 10 primary ccRCC tumors using exome-sequencing. We identified inactivating mutations in VHL, PBRM1, and BAP1. Sequencing of PBRM1 in ccRCC-derived cell lines confirmed its frequent inactivation in ccRCC. PBRM1 encodes for BAF180, the chromatin targeting subunit of the SWI/SNF complex. BAP1 encodes for BRCA1 associated protein-1, involved in histone deubiquitination. Taken together, the accumulating data suggest an important role for aberrant chromatin regulation in ccRCC development.
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands.
authors.forename: Gerben
authors.initials: G
authors.lastname: Duns
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
authors.forename: Jantine G
authors.initials: JG
authors.lastname: Sietzema
authors.forename: Harry
authors.initials: H
authors.lastname: Hollema
authors.forename: Inge
authors.initials: I
authors.lastname: van Duivenbode
authors.forename: Angela
authors.initials: A
authors.lastname: Kuik
authors.forename: Cor
authors.initials: C
authors.lastname: Giezen
authors.forename: Osinga
authors.initials: O
authors.lastname: Jan
authors.forename: Jelkje J
authors.initials: JJ
authors.lastname: Bergsma
authors.forename: Harrie
authors.initials: H
authors.lastname: Bijnen
authors.forename: Pieter
authors.initials: P
authors.lastname: van der Vlies
authors.forename: Eva
authors.initials: E
authors.lastname: van den Berg
authors.forename: Klaas
authors.initials: K
authors.lastname: Kok
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism; D002843:Chromatin / Q000235:genetics / Q000378:metabolism*; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D004268:DNA-Binding Proteins; D059472:Exome / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics
chemical_list: C400134:BAP1 protein, human; D002843:Chromatin; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C102195:PBRM1 protein, human; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human; D043222:Ubiquitin Thiolesterase