Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma

Ignacio Varela; Patrick Tarpey; Keiran Raine; Dachuan Huang; Choon Kiat Ong; Philip Stephens; Helen Davies; David Jones; Meng Lay Lin; Jon Teague; Graham Bignell; Adam Butler; Juok Cho; Gillian L. Dalgliesh; Danushka Galappaththige; Chris Greenman; Claire Hardy; Mingming Jia; Calli Latimer; King Wai Lau; John Marshall; Stuart McLaren; Andrew Menzies; Laura Mudie; Lucy Stebbings; David A. Largaespada; L. F A Wessels; Stephane Richard; Richard J. Kahnoski; John Anema; David A.tuveson; Pedro A. Perez-Mancera; Ville Mustonen; Andrej Fischer; David J. Adams; Alistair Rust; Waraporn Chan-On; Chutima Subimerb; Karl Dykema; Kyle Furge; Peter J. Campbell; Bin Tean Teh; Michael R. Stratton; P. Andrew Futreal

doi:10.1038/nature09639

Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma

Ignacio Varela, Patrick Tarpey, Keiran Raine, Dachuan Huang, Choon Kiat Ong, Philip Stephens, Helen Davies, David Jones, Meng Lay Lin, Jon Teague, Graham Bignell, Adam Butler, Juok Cho, Gillian L. Dalgliesh, Danushka Galappaththige, Chris Greenman, Claire Hardy, Mingming Jia, Calli Latimer, King Wai LauJohn Marshall, Stuart McLaren, Andrew Menzies, Laura Mudie, Lucy Stebbings, David A. Largaespada, L. F A Wessels, Stephane Richard, Richard J. Kahnoski, John Anema, David A.tuveson, Pedro A. Perez-Mancera, Ville Mustonen, Andrej Fischer, David J. Adams, Alistair Rust, Waraporn Chan-On, Chutima Subimerb, Karl Dykema, Kyle Furge, Peter J. Campbell, Bin Tean Teh, Michael R. Stratton, P. Andrew Futreal

Masonic Cancer Center

Research output: Contribution to journal › Article › peer-review

977 Scopus citations

Abstract

The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of ∼3,300 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (also known as KDM6A), JARID1C (also known as KDM5C) and SETD2 (ref. 2). These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodelling complex gene PBRM1 (ref. 4) as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology.

Original language	English (US)
Pages (from-to)	539-542
Number of pages	4
Journal	Nature
Volume	469
Issue number	7331
DOIs	https://doi.org/10.1038/nature09639
State	Published - Jan 27 2011

Bibliographical note

Funding Information:
Acknowledgements P.A.F. and M.R.S. would like to acknowledge the Wellcome Trust for support under grant reference 077012/Z/05/Z and A. Coffey, D. Turner and L. Mamanova for assistance with the exoncapture. K.F., K.D.andB.T.T. acknowledge the support of the Van Andel Research Institute. B.T.T. would like to acknowledge support from the Lee Foundation. I.V. is supported by a fellowship from The International Human Frontier Science Program Organization. D.J.A. acknowledges the support of Cancer Research UK. D.A.T. and P.A.P.-M. acknowledge the support of the University of Cambridge, Cancer Research UK and Hutchison Whampo and thank W. Howatt, A. Hazelhurst and colleagues in the CRI core facilities for their support. B.T.T. would like to dedicate this work to Tat Hock Teh.

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Varela, I., Tarpey, P., Raine, K., Huang, D., Ong, C. K., Stephens, P., Davies, H., Jones, D., Lin, M. L., Teague, J., Bignell, G., Butler, A., Cho, J., Dalgliesh, G. L., Galappaththige, D., Greenman, C., Hardy, C., Jia, M., Latimer, C., ... Futreal, P. A. (2011). Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature, 469(7331), 539-542. https://doi.org/10.1038/nature09639

Varela, I, Tarpey, P, Raine, K, Huang, D, Ong, CK, Stephens, P, Davies, H, Jones, D, Lin, ML, Teague, J, Bignell, G, Butler, A, Cho, J, Dalgliesh, GL, Galappaththige, D, Greenman, C, Hardy, C, Jia, M, Latimer, C, Lau, KW, Marshall, J, McLaren, S, Menzies, A, Mudie, L, Stebbings, L, Largaespada, DA, Wessels, LFA, Richard, S, Kahnoski, RJ, Anema, J, A.tuveson, D, Perez-Mancera, PA, Mustonen, V, Fischer, A, Adams, DJ, Rust, A, Chan-On, W, Subimerb, C, Dykema, K, Furge, K, Campbell, PJ, Teh, BT, Stratton, MR & Futreal, PA 2011, 'Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma', Nature, vol. 469, no. 7331, pp. 539-542. https://doi.org/10.1038/nature09639

@article{133ac45bc80145a08e9e955d7c86cd11,

title = "Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma",

abstract = "The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of ∼3,300 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (also known as KDM6A), JARID1C (also known as KDM5C) and SETD2 (ref. 2). These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodelling complex gene PBRM1 (ref. 4) as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology.",

author = "Ignacio Varela and Patrick Tarpey and Keiran Raine and Dachuan Huang and Ong, {Choon Kiat} and Philip Stephens and Helen Davies and David Jones and Lin, {Meng Lay} and Jon Teague and Graham Bignell and Adam Butler and Juok Cho and Dalgliesh, {Gillian L.} and Danushka Galappaththige and Chris Greenman and Claire Hardy and Mingming Jia and Calli Latimer and Lau, {King Wai} and John Marshall and Stuart McLaren and Andrew Menzies and Laura Mudie and Lucy Stebbings and Largaespada, {David A.} and Wessels, {L. F A} and Stephane Richard and Kahnoski, {Richard J.} and John Anema and David A.tuveson and Perez-Mancera, {Pedro A.} and Ville Mustonen and Andrej Fischer and Adams, {David J.} and Alistair Rust and Waraporn Chan-On and Chutima Subimerb and Karl Dykema and Kyle Furge and Campbell, {Peter J.} and Teh, {Bin Tean} and Stratton, {Michael R.} and Futreal, {P. Andrew}",

note = "Funding Information: Acknowledgements P.A.F. and M.R.S. would like to acknowledge the Wellcome Trust for support under grant reference 077012/Z/05/Z and A. Coffey, D. Turner and L. Mamanova for assistance with the exoncapture. K.F., K.D.andB.T.T. acknowledge the support of the Van Andel Research Institute. B.T.T. would like to acknowledge support from the Lee Foundation. I.V. is supported by a fellowship from The International Human Frontier Science Program Organization. D.J.A. acknowledges the support of Cancer Research UK. D.A.T. and P.A.P.-M. acknowledge the support of the University of Cambridge, Cancer Research UK and Hutchison Whampo and thank W. Howatt, A. Hazelhurst and colleagues in the CRI core facilities for their support. B.T.T. would like to dedicate this work to Tat Hock Teh.",

year = "2011",

month = jan,

day = "27",

doi = "10.1038/nature09639",

language = "English (US)",

volume = "469",

pages = "539--542",

journal = "Nature",

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T1 - Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma

AU - Varela, Ignacio

AU - Tarpey, Patrick

AU - Raine, Keiran

AU - Huang, Dachuan

AU - Ong, Choon Kiat

AU - Stephens, Philip

AU - Davies, Helen

AU - Jones, David

AU - Lin, Meng Lay

AU - Teague, Jon

AU - Bignell, Graham

AU - Butler, Adam

AU - Cho, Juok

AU - Dalgliesh, Gillian L.

AU - Galappaththige, Danushka

AU - Greenman, Chris

AU - Hardy, Claire

AU - Jia, Mingming

AU - Latimer, Calli

AU - Lau, King Wai

AU - Marshall, John

AU - McLaren, Stuart

AU - Menzies, Andrew

AU - Mudie, Laura

AU - Stebbings, Lucy

AU - Largaespada, David A.

AU - Wessels, L. F A

AU - Richard, Stephane

AU - Kahnoski, Richard J.

AU - Anema, John

AU - A.tuveson, David

AU - Perez-Mancera, Pedro A.

AU - Mustonen, Ville

AU - Fischer, Andrej

AU - Adams, David J.

AU - Rust, Alistair

AU - Chan-On, Waraporn

AU - Subimerb, Chutima

AU - Dykema, Karl

AU - Furge, Kyle

AU - Campbell, Peter J.

AU - Teh, Bin Tean

AU - Stratton, Michael R.

AU - Futreal, P. Andrew

N1 - Funding Information: Acknowledgements P.A.F. and M.R.S. would like to acknowledge the Wellcome Trust for support under grant reference 077012/Z/05/Z and A. Coffey, D. Turner and L. Mamanova for assistance with the exoncapture. K.F., K.D.andB.T.T. acknowledge the support of the Van Andel Research Institute. B.T.T. would like to acknowledge support from the Lee Foundation. I.V. is supported by a fellowship from The International Human Frontier Science Program Organization. D.J.A. acknowledges the support of Cancer Research UK. D.A.T. and P.A.P.-M. acknowledge the support of the University of Cambridge, Cancer Research UK and Hutchison Whampo and thank W. Howatt, A. Hazelhurst and colleagues in the CRI core facilities for their support. B.T.T. would like to dedicate this work to Tat Hock Teh.

PY - 2011/1/27

Y1 - 2011/1/27

N2 - The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of ∼3,300 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (also known as KDM6A), JARID1C (also known as KDM5C) and SETD2 (ref. 2). These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodelling complex gene PBRM1 (ref. 4) as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology.

AB - The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of ∼3,300 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (also known as KDM6A), JARID1C (also known as KDM5C) and SETD2 (ref. 2). These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodelling complex gene PBRM1 (ref. 4) as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology.

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Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma

Abstract

Bibliographical note

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