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

A Corrigendum to this article was published on 28 March 2012


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 3,500 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (also known as KDM6A)1, 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 control3. 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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Figure 1: PBRM1 somatic mutations.
Figure 2: Analysis of PBRM1 missense mutations.
Figure 3: Pbrm1 is frequently mutated in a mouse model of pancreatic cancer.
Figure 4: Knockdown of PBRM1 expression in RCC cell lines.

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Primary accessions

Gene Expression Omnibus

Data deposits

Exome sequence data have been deposited at the European Genome-Phenome Archive ( hosted by the European Bioinformatics Institute under accession EGAS00001000006 and expression data has been deposited with Gene Expression Omnibus ( under accession GSE22316.


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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 exon capture. K.F., K.D. and B.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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Authors and Affiliations



I.V. and P.T. performed the main analytical aspects of the study. P.S., H.D., G.L.D., M.-L.L., G.B., C.H., L.M., S.M. performed the follow-up sequencing and analyses. K.R., D.J., J.T., A.B., C.G., D.G., M.J., C.L., J.M., A.M., L.S. contributed to the data processing, mapping and variant calling informatics. C.G. and K.W.L. performed statistical analyses. S.R., R.J.K., J.A. contributed samples and data for the clinical series. D.J.A., A.R., D.A.L., L.F.A.W., D.A.T., P.A.P.-M. performed the transposon screening and analyses. D.H., C.K.O., W.C., C.S. performed the siRNA and functional work. V.M., A.F. performed the missense mutation analysis. K.D., K.F. and J.C. performed the expression analyses. P.J.C., B.T.T., M.R.S., P.A.F. directed the study and wrote the manuscript, which all authors have approved.

Corresponding authors

Correspondence to Bin Tean Teh, Michael R. Stratton or P. Andrew Futreal.

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The authors declare no competing financial interests.

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This file contains Supplementary Methods and Data, additional references and Supplementary Tables 1-8. (PDF 2531 kb)

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Varela, I., Tarpey, P., Raine, K. et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469, 539–542 (2011).

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