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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

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.

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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 (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

  1. van Haaften, G. et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nature Genet. 41, 521–523 (2009)

    Article  CAS  PubMed  Google Scholar 

  2. Dalgliesh, G. L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007)

    Article  CAS  PubMed  Google Scholar 

  4. Thompson, M. Polybromo-1: the chromatin targeting subunit of the PBAF complex. Biochimie 91, 309–319 (2009)

    Article  CAS  PubMed  Google Scholar 

  5. Gnirke, A. et al. Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nature Biotechnol. 27, 182–189 (2009)

    Article  CAS  Google Scholar 

  6. 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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Reisman, D., Glaros, S. & Thompson, E. A. The SWI/SNF complex and cancer. Oncogene 28, 1653–1668 (2009)

    Article  CAS  PubMed  Google Scholar 

  8. 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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Versteege, I. et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394, 203–206 (1998)

    Article  ADS  CAS  PubMed  Google Scholar 

  10. 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)

    CAS  PubMed  Google Scholar 

  11. Chandrasekaran, R. & Thompson, M. Polybromo-1-bromodomains bind histone H3 at specific acetyl-lysine positions. Biochem. Biophys. Res. Commun. 355, 661–666 (2007)

    Article  CAS  PubMed  Google Scholar 

  12. 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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Sekine, I. et al. The 3p21 candidate tumor suppressor gene BAF180 is normally expressed in human lung cancer. Oncogene 24, 2735–2738 (2005)

    Article  CAS  PubMed  Google Scholar 

  14. Jones, S. et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science 321, 1801–1806 (2008)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  15. 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)

    Article  CAS  Google Scholar 

  16. Hingorani, S. R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003)

    Article  CAS  PubMed  Google Scholar 

  17. Starr, T. K. et al. A transposon-based genetic screen in mice identifies genes altered in colorectal cancer. Science 323, 1747–1750 (2009)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  18. 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)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  19. 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)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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)

    Article  CAS  PubMed  Google Scholar 

  22. 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)

    Article  ADS  CAS  PubMed  Google Scholar 

  23. 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)

    Article  CAS  PubMed  Google Scholar 

  24. 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)

    Article  CAS  PubMed  Google Scholar 

  25. 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)

    Article  CAS  PubMed  Google Scholar 

  26. Jones, S. et al. Frequent mutations of chromatin remodeling gene ARID1A in ovarian clear cell carcinoma. Science 330, 228–231 (2010)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wiegand, K. C. et al. ARID1A mutations in endometriosis-associated ovarian carcinomas. N. Engl. J. Med. 363, 1532–1543 (2010)

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 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)

    Article  CAS  PubMed  Google Scholar 

  29. 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)

    Article  ADS  CAS  PubMed  Google Scholar 

  30. 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)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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.

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Authors and Affiliations

Authors

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

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). https://doi.org/10.1038/nature09639

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