Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes

Gillian L. Dalgliesh; Kyle Furge; Chris Greenman; Lina Chen; Graham Bignell; Adam Butler; Helen Davies; Sarah Edkins; Claire Hardy; Calli Latimer; Jon Teague; Jenny Andrews; Syd Barthorpe; Dave Beare; Gemma Buck; Peter J. Campbell; Simon Forbes; Mingming Jia; David Jones; Henry Knott; Chai Yin Kok; King Wai Lau; Catherine Leroy; Meng-Lay Lin; David J. McBride; Mark Maddison; Simon Maguire; Kirsten McLay; Andrew Menzies; Tatiana Mironenko; Lee Mulderrig; Laura Mudie; Sarah O'Meara; Erin Pleasance; Aarjunan Rajasingham; Rebecca Shepherd; Raffaella Smith; Lucy Stebbings; Philip Stephens; Gurpreet Tang; Patrick S. Tarpey; Kelly Turrell; Karl J. Dykema; Sok Kean Khoo; David Petillo; Bill Wondergem; John Anema; Richard J. Kahnoski; Bin Tean Teh; Michael R. Stratton; P. Andrew Futreal

doi:10.1038/nature08672

Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes

Gillian L. Dalgliesh, Kyle Furge, Chris Greenman, Lina Chen, Graham Bignell, Adam Butler, Helen Davies, Sarah Edkins, Claire Hardy, Calli Latimer, Jon Teague, Jenny Andrews, Syd Barthorpe, Dave Beare, Gemma Buck, Peter J. Campbell, Simon Forbes, Mingming Jia, David Jones, Henry KnottChai Yin Kok, King Wai Lau, Catherine Leroy, Meng-Lay Lin, David J. McBride, Mark Maddison, Simon Maguire, Kirsten McLay, Andrew Menzies, Tatiana Mironenko, Lee Mulderrig, Laura Mudie, Sarah O'Meara, Erin Pleasance, Aarjunan Rajasingham, Rebecca Shepherd, Raffaella Smith, Lucy Stebbings, Philip Stephens, Gurpreet Tang, Patrick S. Tarpey, Kelly Turrell, Karl J. Dykema, Sok Kean Khoo, David Petillo, Bill Wondergem, John Anema, Richard J. Kahnoski, Bin Tean Teh, Michael R. Stratton, P. Andrew Futreal

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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.

Original language	English
Pages (from-to)	360-363
Number of pages	4
Journal	Nature
Volume	463
Issue number	7279
DOIs	https://doi.org/10.1038/nature08672
Publication status	Published - 21 Jan 2010

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Dalgliesh, G. L., Furge, K., Greenman, C., Chen, L., Bignell, G., Butler, A., Davies, H., Edkins, S., Hardy, C., Latimer, C., Teague, J., Andrews, J., Barthorpe, S., Beare, D., Buck, G., Campbell, P. J., Forbes, S., Jia, M., Jones, D., ... Futreal, P. A. (2010). Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature, 463(7279), 360-363. https://doi.org/10.1038/nature08672

@article{650c850c9db14a7196d1cca63b15bc6b,

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.",

author = "Dalgliesh, {Gillian L.} and Kyle Furge and Chris Greenman and Lina Chen and Graham Bignell and Adam Butler and Helen Davies and Sarah Edkins and Claire Hardy and Calli Latimer and Jon Teague and Jenny Andrews and Syd Barthorpe and Dave Beare and Gemma Buck and Campbell, {Peter J.} and Simon Forbes and Mingming Jia and David Jones and Henry Knott and Kok, {Chai Yin} and Lau, {King Wai} and Catherine Leroy and Meng-Lay Lin and McBride, {David J.} and Mark Maddison and Simon Maguire and Kirsten McLay and Andrew Menzies and Tatiana Mironenko and Lee Mulderrig and Laura Mudie and Sarah O'Meara and Erin Pleasance and Aarjunan Rajasingham and Rebecca Shepherd and Raffaella Smith and Lucy Stebbings and Philip Stephens and Gurpreet Tang and Tarpey, {Patrick S.} and Kelly Turrell and Dykema, {Karl J.} and Khoo, {Sok Kean} and David Petillo and Bill Wondergem and John Anema and Kahnoski, {Richard J.} and Teh, {Bin Tean} and Stratton, {Michael R.} and Futreal, {P. Andrew}",

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Dalgliesh, GL, Furge, K, Greenman, C, Chen, L, Bignell, G, Butler, A, Davies, H, Edkins, S, Hardy, C, Latimer, C, Teague, J, Andrews, J, Barthorpe, S, Beare, D, Buck, G, Campbell, PJ, Forbes, S, Jia, M, Jones, D, Knott, H, Kok, CY, Lau, KW, Leroy, C, Lin, M-L, McBride, DJ, Maddison, M, Maguire, S, McLay, K, Menzies, A, Mironenko, T, Mulderrig, L, Mudie, L, O'Meara, S, Pleasance, E, Rajasingham, A, Shepherd, R, Smith, R, Stebbings, L, Stephens, P, Tang, G, Tarpey, PS, Turrell, K, Dykema, KJ, Khoo, SK, Petillo, D, Wondergem, B, Anema, J, Kahnoski, RJ, Teh, BT, Stratton, MR & Futreal, PA 2010, 'Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes', Nature, vol. 463, no. 7279, pp. 360-363. https://doi.org/10.1038/nature08672

TY - JOUR

T1 - Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes

AU - Dalgliesh, Gillian L.

AU - Furge, Kyle

AU - Greenman, Chris

AU - Chen, Lina

AU - Bignell, Graham

AU - Butler, Adam

AU - Davies, Helen

AU - Edkins, Sarah

AU - Hardy, Claire

AU - Latimer, Calli

AU - Teague, Jon

AU - Andrews, Jenny

AU - Barthorpe, Syd

AU - Beare, Dave

AU - Buck, Gemma

AU - Campbell, Peter J.

AU - Forbes, Simon

AU - Jia, Mingming

AU - Jones, David

AU - Knott, Henry

AU - Kok, Chai Yin

AU - Lau, King Wai

AU - Leroy, Catherine

AU - Lin, Meng-Lay

AU - McBride, David J.

AU - Maddison, Mark

AU - Maguire, Simon

AU - McLay, Kirsten

AU - Menzies, Andrew

AU - Mironenko, Tatiana

AU - Mulderrig, Lee

AU - Mudie, Laura

AU - O'Meara, Sarah

AU - Pleasance, Erin

AU - Rajasingham, Aarjunan

AU - Shepherd, Rebecca

AU - Smith, Raffaella

AU - Stebbings, Lucy

AU - Stephens, Philip

AU - Tang, Gurpreet

AU - Tarpey, Patrick S.

AU - Turrell, Kelly

AU - Dykema, Karl J.

AU - Khoo, Sok Kean

AU - Petillo, David

AU - Wondergem, Bill

AU - Anema, John

AU - Kahnoski, Richard J.

AU - Teh, Bin Tean

AU - Stratton, Michael R.

AU - Futreal, P. Andrew

PY - 2010/1/21

Y1 - 2010/1/21

N2 - 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.

AB - 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.

U2 - 10.1038/nature08672

DO - 10.1038/nature08672

M3 - Article

SN - 1476-4687

VL - 463

SP - 360

EP - 363

JO - Nature

JF - Nature

IS - 7279

ER -