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 ∼3,500 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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
Primary accessions
Gene Expression Omnibus
Data deposits
Exome sequence data have been deposited at the European Genome-Phenome Archive (http://www.ebi.ac.uk/ega/) hosted by the European Bioinformatics Institute under accession EGAS00001000006 and expression data has been deposited with Gene Expression Omnibus (http://www.ncbi.nlm.nih.gov/geo/) under accession GSE22316.
References
van Haaften, G. et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nature Genet. 41, 521–523 (2009)
Dalgliesh, G. L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010)
Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007)
Thompson, M. Polybromo-1: the chromatin targeting subunit of the PBAF complex. Biochimie 91, 309–319 (2009)
Gnirke, A. et al. Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nature Biotechnol. 27, 182–189 (2009)
Ye, K., Schulz, M. H., Long, Q., Apweiler, R. & Ning, Z. Pindel: a pattern growth approach to detect break points of large deletions and medium sized insertions from paired-end short reads. Bioinformatics 25, 2865–2871 (2009)
Reisman, D., Glaros, S. & Thompson, E. A. The SWI/SNF complex and cancer. Oncogene 28, 1653–1668 (2009)
Schneppenheim, R. et al. Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome. Am. J. Hum. Genet. 86, 279–284 (2010)
Versteege, I. et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394, 203–206 (1998)
Wong, A. K. C. et al. BRG1, a component of the SWI-SNF complex, is mutated in multiple human tumor cell lines. Cancer Res. 60, 6171–6177 (2000)
Chandrasekaran, R. & Thompson, M. Polybromo-1-bromodomains bind histone H3 at specific acetyl-lysine positions. Biochem. Biophys. Res. Commun. 355, 661–666 (2007)
Xia, W. et al. BAF180 is a critical regulator of p21 induction and a tumor suppressor mutated in breast cancer. Cancer Res. 68, 1667–1674 (2008)
Sekine, I. et al. The 3p21 candidate tumor suppressor gene BAF180 is normally expressed in human lung cancer. Oncogene 24, 2735–2738 (2005)
Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008)
Keng, V. W. et al. A conditional transposon-based insertional mutagenesis screen for genes associated with mouse hepatocellular carcinoma. Nature Biotechnol. 27, 264–274 (2009)
Hingorani, S. R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003)
Starr, T. K. et al. A transposon-based genetic screen in mice identifies genes altered in colorectal cancer. Science 323, 1747–1750 (2009)
Burrows, A. E., Smogorzewska, A. & Elledge, S. J. Polybromo-associated BRG1-associated factor components BRD7 and BAF180 are critical regulators of p53 required for induction of replicative senescence. Proc. Natl Acad. Sci. USA 107, 14280–14285 (2010)
Xue, Y. et al. The human SWI/SNF-B chromatin-remodeling complex is related to yeast Rsc and localizes at kinetochores of mitotic chromosomes. Proc. Natl Acad. Sci. USA 97, 13015–13020 (2000)
Vries, R. G. J. et al. Cancer-associated mutations in chromatin remodeler hSNF5 promote chromosomal instability by compromising the mitotic checkpoint. Genes Dev. 19, 665–670 (2005)
Mandriota, S. J. et al. HIF activation identifies early lesions in VHL kidneys: evidence for site-specific tumor suppressor function in the nephron. Cancer Cell 1, 459–468 (2002)
Young, A. P. et al. VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. Nature Cell Biol. 10, 361–369 (2008)
Clifford, S. C., Prowse, A. H., Affara, N. A., Buys, C. H. C. M. & Maher, E. R. Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene and allelic losses at chromosome arm 3p in primary renal cell carcinoma: evidence for a VHL-independent pathway in clear cell renal tumourigenesis. Genes Chromosom. Cancer 22, 200–209 (1998)
Kenneth, N. S., Mudie, S., van Uden, P. & Rocha, S. SWI/SNF regulates the cellular response to hypoxia. J. Biol. Chem. 284, 4123–4131 (2009)
Wang, X. et al. Expression of p270 (ARID1A), a component of human SWI/SNF complexes, in human tumors. Int. J. Cancer 112, 636–642 (2004)
Jones, S. et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330, 228–231 (2010)
Wiegand, K. C. et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N. Engl. J. Med. 363, 1532–1543 (2010)
Papaemmanuil, E. et al. Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia. Nature Genet. 41, 1006–1010 (2009)
Collier, L. S., Carlson, C. M., Ravimohan, S., Dupuy, A. J. & Largaespada, D. A. Cancer gene discovery in solid tumours using transposon-based somatic mutagenesis in the mouse. Nature 436, 272–276 (2005)
Uren, A. G. et al. Large-scale mutagenesis in p19ARF - and p53-deficient mice identifies cancer genes and their collaborative networks. Cell 133, 727–741 (2008)
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 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.
Author information
Authors and Affiliations
Contributions
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
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Information
This file contains Supplementary Methods and Data, additional references and Supplementary Tables 1-8. (PDF 2531 kb)
Rights and permissions
About this article
Cite this article
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). https://doi.org/10.1038/nature09639
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature09639
This article is cited by
-
Systematic analysis of RNASET2 gene as a potential prognostic and immunological biomarker in clear cell renal cell carcinoma
BMC Cancer (2023)
-
Prognostic and predictive biomarkers for immunotherapy in advanced renal cell carcinoma
Nature Reviews Urology (2023)
-
PBRM1 loss redirects chromatin remodelling complex to recruit oncogenic factors
Nature Cell Biology (2023)
-
Predictive genomic biomarkers of therapeutic effects in renal cell carcinoma
Cellular Oncology (2023)
-
PBRM1-deficient PBAF complexes target aberrant genomic loci to activate the NF-κB pathway in clear cell renal cell carcinoma
Nature Cell Biology (2023)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.
