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 ∼3,300 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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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 exoncapture. K.F., K.D.andB.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.