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. 2011 Jan 27;469(7331):539-42.
doi: 10.1038/nature09639. Epub 2011 Jan 19.

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

Ignacio Varela  1 , 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
Affiliations

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

Ignacio Varela et al. Nature. .

Erratum in

  • Nature. 2012 Apr 5;484(7392):130

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), 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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Figures

Figure 1
Figure 1. PBRM1 somatic mutations
Representation of PBRM1 transcript with boxes BR1-BR6, BAH1-2 and HMG indicating the positions of the bromodomains 1-6, bromo-adjacent homology domains and high-mobility group domain, respectively. Relative positions of mutations are indicated by symbols. Stars – nonsense, dots – missense, red triangles – frameshift deletions, black triangles – frameshift insertions and green triangles – in-frame deletions. Splice-site mutations are not depicted.
Figure 2
Figure 2. Analysis of PBRM1 missense mutations
Bars represent histogram of the mean score of in silico generated random missense mutations (10,000 sets of three mutations that can be scored) and the red circle denotes the mean score of the somatic mutations that could be scored (T232P □s = −7.78, A597D □s = −9.69, H1204P □s = −2.76). The somatic set is significantly different from the null set (p-value 0.01). They have a higher negative mean score and are thus predicted to be more deleterious on average.
Figure 3
Figure 3. Pbrm1 is frequently mutated in a mouse model of pancreatic cancer
To identify genes that co-operate with K-Ras in the formation of pancreatic cancer a conditional allele of K-RasG12D and Pdx1-Cre were combined with a conditional Sleeping Beauty transposase driver and the T2Onctg transposon donor allele. Expression of Cre results in expression of K-RasG12D and transposon mobilization within the epithelial compartment of the pancreas. Isolation of the transposon insertion sites from a panel of 153 pancreatic cancers and pre-neoplastic lesions generated from this model revealed a common insertion site in Pbrm1 suggesting that loss of Pbrm1 co-operates with K-RasG12D in pancreatic cancer development. Statistical analysis was performed as previously described. Transposon insertions in the forward strand of Pbrm1 are shown in green. Insertions in the reverse orientation are shown in red. A chromatogram from sequencing of RT-PCR products from one tumour is shown demonstrating splicing of exon 24 of Pbrm1 into the inserted transposon, thus truncating the transcript.
Figure 4
Figure 4. Knockdown of PBRM1 expression in RCC cell lines
(A) Verification of PBRM1 knockdown by western blotting. (B)Silencing PBRM1 increased the proliferation of ACHN and 786-O with wild type PBRM1, but not A704 with a homozygous PBRM1 truncating mutation. Data represent means of triplicate experiments with standard deviation, p<0.01. (C) Knockdown of PBRM1 enhanced colony formation in SN12C cells. Data represent means of triplicate experiments with standard deviation, p<0.01. (D) Knockdown of PBRM1 enhanced cell migration in 786-O, SN12C and TK10 cells. Data represent means of triplicate experiments with standard deviation, p<0.01. (E) Gene sets that are most significantly deregulated following PBRM1 knockdown in three RCC cell lines using curated gene sets obtained from MSigDB (http://www.broadinstitute.org/gsea/msigdb/) and additional curated gene sets obtained from the PGSEA package (see Supplemental Material for details).
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References

    1. van Haaften G, et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat Genet. 2009;41:521–3. - PMC - PubMed
    1. Dalgliesh GL, et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature. 2010;463:360–363. - PMC - PubMed
    1. Kouzarides T. Chromatin Modifications and Their Function. Cell. 2007;128:693–705. - PubMed
    1. Thompson M. Polybromo-1: The chromatin targeting subunit of the PBAF complex. Biochimie. 2009;91:309–319. - PMC - PubMed
    1. Gnirke A, et al. Solution hybrid selection with ultra-long oligonucleotides for massively parallel targeted sequencing. Nat Biotech. 2009;27:182–189. - PMC - PubMed

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