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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.

SUBMITTER: Dalgliesh GL

PROVIDER: S-EPMC2820242 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes.

Dalgliesh Gillian L GL Furge Kyle K Greenman Chris C Chen Lina L Bignell Graham G Butler Adam A Davies Helen H Edkins Sarah S Hardy Claire C Latimer Calli C Teague Jon J Andrews Jenny J Barthorpe Syd S Beare Dave D Buck Gemma G Campbell Peter J PJ Forbes Simon S Jia Mingming M Jones David D Knott Henry H Kok Chai Yin CY Lau King Wai KW Leroy Catherine C Lin Meng-Lay ML McBride David J DJ Maddison Mark M Maguire Simon S McLay Kirsten K Menzies Andrew A Mironenko Tatiana T Mulderrig Lee L Mudie Laura L O'Meara Sarah S Pleasance Erin E Rajasingham Arjunan A Shepherd Rebecca R Smith Raffaella R Stebbings Lucy L Stephens Philip P Tang Gurpreet G Tarpey Patrick S PS Turrell Kelly K Dykema Karl J KJ Khoo Sok Kean SK Petillo David D Wondergem Bill B Anema John J Kahnoski Richard J RJ Teh Bin Tean BT Stratton Michael R MR Futreal P Andrew PA

Nature 20100106 7279

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 methy ...[more]

PMID: 20054297

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Project description:Ischemic renal injury can produce chronic renal inflammation and fibrosis. This study tested whether ischemia-reperfusion (I/R) activates histone-modifying enzyme systems and alters histone expression at selected proinflammatory/profibrotic genes. CD-1 mice were subjected to 30 min of unilateral I/R. Contralateral kidneys served as controls. At 1, 3, or 7 days of reflow, bilateral nephrectomy was performed. Renal cortices were probed for monocyte chemoattractant protein-1 (MCP-1), transforming growth factor-beta1 (TGF-beta1), and collagen III mRNAs and cytokine levels. RNA polymerase II (Pol II) binding, which initiates transcription, was quantified at exon 1 of the MCP-1, TGF-beta1, collagen III genes (chromatin immunoprecipitation assay). Two representative gene-activating histone modifications [histone 3 lysine 4 (H3K4) trimethylation (m3) (H3K4m3); histone 2 variant H2A.Z] were sought. Degrees of binding of two relevant histone-modifying enzymes (Set1, BRG1) to target genes were assessed. Renal cortical Set1, BRG1, and H2A.Z mRNAs were measured. Finally, the potential utility of urinary mRNA concentrations as noninvasive markers of these in vivo processes was tested. I/R caused progressive increases in Pol II binding to MCP-1, TGF-beta1, and collagen III genes. Parallel increases in cognate mRNAs also were expressed. Progressive increases in renal cortical Set1, BRG1, H2A.Z mRNAs, and increased Set1/BRG1 binding to target genes occurred. These changes corresponded with: 1) progressive elevations of H3K4m3 and H2A.Z at each test gene; 2) increases in renal cortical TGF-beta1/MCP-1 cytokines; and 3) renal collagen deposition (assessed by histomorphology). Postischemic increases in urinary TGF-beta1, MCP-1, Set1, and BRG1 mRNAs were also observed. We conclude that: 1) I/R upregulates histone-modifying enzyme systems, 2) histone modifications at proinflammatory/profibrotic genes can result, and 3) urinary mRNA assessments may have utility for noninvasive monitoring of these in vivo events.

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Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes.

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Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes.

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