title: Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes.
abstract: Clear cell renal cell carcinoma (ccRCC) is the most common form of adult kidney cancer, characterized by the presence of inactivating mutations in the VHL gene in most cases, and by infrequent somatic mutations in known cancer genes. To determine further the genetics of ccRCC, we have sequenced 101 cases through 3,544 protein-coding genes. Here we report the identification of inactivating mutations in two genes encoding enzymes involved in histone modification-SETD2, a histone H3 lysine 36 methyltransferase, and JARID1C (also known as KDM5C), a histone H3 lysine 4 demethylase-as well as mutations in the histone H3 lysine 27 demethylase, UTX (KMD6A), that we recently reported. The results highlight the role of mutations in components of the chromatin modification machinery in human cancer. Furthermore, NF2 mutations were found in non-VHL mutated ccRCC, and several other probable cancer genes were identified. These results indicate that substantial genetic heterogeneity exists in a cancer type dominated by mutations in a single gene, and that systematic screens will be key to fully determining the somatic genetic architecture of cancer.
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Gillian L
authors.initials: GL
authors.lastname: Dalgliesh
authors.forename: Kyle
authors.initials: K
authors.lastname: Furge
authors.forename: Chris
authors.initials: C
authors.lastname: Greenman
authors.forename: Lina
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authors.lastname: Chen
authors.forename: Graham
authors.initials: G
authors.lastname: Bignell
authors.forename: Adam
authors.initials: A
authors.lastname: Butler
authors.forename: Helen
authors.initials: H
authors.lastname: Davies
authors.forename: Sarah
authors.initials: S
authors.lastname: Edkins
authors.forename: Claire
authors.initials: C
authors.lastname: Hardy
authors.forename: Calli
authors.initials: C
authors.lastname: Latimer
authors.forename: Jon
authors.initials: J
authors.lastname: Teague
authors.forename: Jenny
authors.initials: J
authors.lastname: Andrews
authors.forename: Syd
authors.initials: S
authors.lastname: Barthorpe
authors.forename: Dave
authors.initials: D
authors.lastname: Beare
authors.forename: Gemma
authors.initials: G
authors.lastname: Buck
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.forename: Simon
authors.initials: S
authors.lastname: Forbes
authors.forename: Mingming
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authors.lastname: Jia
authors.forename: David
authors.initials: D
authors.lastname: Jones
authors.forename: Henry
authors.initials: H
authors.lastname: Knott
authors.forename: Chai Yin
authors.initials: CY
authors.lastname: Kok
authors.forename: King Wai
authors.initials: KW
authors.lastname: Lau
authors.forename: Catherine
authors.initials: C
authors.lastname: Leroy
authors.forename: Meng-Lay
authors.initials: ML
authors.lastname: Lin
authors.forename: David J
authors.initials: DJ
authors.lastname: McBride
authors.forename: Mark
authors.initials: M
authors.lastname: Maddison
authors.forename: Simon
authors.initials: S
authors.lastname: Maguire
authors.forename: Kirsten
authors.initials: K
authors.lastname: McLay
authors.forename: Andrew
authors.initials: A
authors.lastname: Menzies
authors.forename: Tatiana
authors.initials: T
authors.lastname: Mironenko
authors.forename: Lee
authors.initials: L
authors.lastname: Mulderrig
authors.forename: Laura
authors.initials: L
authors.lastname: Mudie
authors.forename: Sarah
authors.initials: S
authors.lastname: O'Meara
authors.forename: Erin
authors.initials: E
authors.lastname: Pleasance
authors.forename: Arjunan
authors.initials: A
authors.lastname: Rajasingham
authors.forename: Rebecca
authors.initials: R
authors.lastname: Shepherd
authors.forename: Raffaella
authors.initials: R
authors.lastname: Smith
authors.forename: Lucy
authors.initials: L
authors.lastname: Stebbings
authors.forename: Philip
authors.initials: P
authors.lastname: Stephens
authors.forename: Gurpreet
authors.initials: G
authors.lastname: Tang
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Tarpey
authors.forename: Kelly
authors.initials: K
authors.lastname: Turrell
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Dykema
authors.forename: Sok Kean
authors.initials: SK
authors.lastname: Khoo
authors.forename: David
authors.initials: D
authors.lastname: Petillo
authors.forename: Bill
authors.initials: B
authors.lastname: Wondergem
authors.forename: John
authors.initials: J
authors.lastname: Anema
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Kahnoski
authors.forename: Bin Tean
authors.initials: BT
authors.lastname: Teh
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
mesh_terms: D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D015687:Cell Hypoxia / Q000235:genetics; D002843:Chromatin / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D016515:Genes, Neurofibromatosis 2; D056466:Histone Demethylases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D002843:Chromatin; D006657:Histones; D009687:Nuclear Proteins; D056466:Histone Demethylases; C086877:KDM5C protein, human; C523998:KDM6A protein, human; D010089:Oxidoreductases, N-Demethylating; D011495:Histone-Lysine N-Methyltransferase; C521636:SETD2 protein, human