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

Research output: Contribution to journalArticle

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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 languageEnglish (US)
Pages (from-to)539-542
Number of pages4
JournalNature
Volume469
Issue number7331
DOIs
StatePublished - Jan 27 2011

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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