Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinomaExome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinomaVarela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, Davies H, Jones D, Lin ML, Teague J, Bignell G, Butler A, Cho J, Dalgliesh GL, Galappaththige D, Greenman C, Hardy C, Jia M, Latimer C, Lau KW, Marshall J, McLaren S, Menzies A, Mudie L, Stebbin2011-01-26T23:00:00Z<p style="text-align:justify;"><strong class="ms-rteThemeFontFace-1 ms-rteFontSize-2">​Abstract</strong></p><p style="text-align:justify;"><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;">The genetics of renal cancer is dominated by inactivation of the </span><em class="ms-rteThemeFontFace-1 ms-rteFontSize-2">VHL</em><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;">tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of </span><span class="stix ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;"><span class="stix ms-rteThemeFontFace-1 ms-rteFontSize-2">∼</span></span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;">3,500 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including </span><em class="ms-rteThemeFontFace-1 ms-rteFontSize-2">UTX</em><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;"> (also known as </span><em class="ms-rteThemeFontFace-1 ms-rteFontSize-2">KDM6A</em><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;">)</span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="line-height:0;vertical-align:baseline;top:-0.5em;color:#222222;letter-spacing:0.17000000178813934px;"><a title="van Haaften, G. et al. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nature Genet. 41, 521–523 (2009)" href="https://www.nature.com/articles/nature09639#ref1" aria-label="Reference 1" data-track="click" data-track-action="reference anchor" data-track-label="link" style="background-color:transparent;color:#006699;vertical-align:baseline;">1</a></span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;">, </span><em class="ms-rteThemeFontFace-1 ms-rteFontSize-2">JARID1C</em><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;"> (also known as </span><em class="ms-rteThemeFontFace-1 ms-rteFontSize-2">KDM5C</em><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;">) and </span><em class="ms-rteThemeFontFace-1 ms-rteFontSize-2">SETD2</em><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;"> (ref. </span><a title="Dalgliesh, G. L. et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463, 360–363 (2010)" href="https://www.nature.com/articles/nature09639#ref2" aria-label="Reference 2" data-track="click" data-track-action="reference anchor" data-track-label="link" style="background-color:transparent;color:#006699;vertical-align:baseline;letter-spacing:0.17000000178813934px;"><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2">2</span></a><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;">). These genes encode enzymes that demethylate (</span><em class="ms-rteThemeFontFace-1 ms-rteFontSize-2">UTX</em><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;">, </span><em class="ms-rteThemeFontFace-1 ms-rteFontSize-2">JARID1C</em><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;">) or methylate (</span><em class="ms-rteThemeFontFace-1 ms-rteFontSize-2">SETD2</em><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;">) 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</span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="line-height:0;vertical-align:baseline;top:-0.5em;color:#222222;letter-spacing:0.17000000178813934px;"><a title="Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007)" href="https://www.nature.com/articles/nature09639#ref3" aria-label="Reference 3" data-track="click" data-track-action="reference anchor" data-track-label="link" style="background-color:transparent;color:#006699;vertical-align:baseline;">3</a></span><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;">. 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 </span><em class="ms-rteThemeFontFace-1 ms-rteFontSize-2">PBRM1</em><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;"> (ref. </span><a title="Thompson, M. Polybromo-1: the chromatin targeting subunit of the PBAF complex. Biochimie 91, 309–319 (2009)" href="https://www.nature.com/articles/nature09639#ref4" aria-label="Reference 4" data-track="click" data-track-action="reference anchor" data-track-label="link" style="background-color:transparent;color:#006699;vertical-align:baseline;letter-spacing:0.17000000178813934px;"><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2">4</span></a><span class="ms-rteThemeFontFace-1 ms-rteFontSize-2" style="color:#222222;letter-spacing:0.17000000178813934px;background-color:#ffffff;">) 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.</span><br></p><p><a href="https://www.nature.com/articles/nature09639">Nature (2011) 469:539-542.</a><br></p>195