Subsequent mutations or chromosomal copy number alterations in epigenetic regulatory genes (including PBRM1, BAP1, SETD2, and KDM5C), cell-cycle regulatory genes (including TP53, CDKN2A, and MYC) or PI3K pathway genes (including PIK3CA, PTEN, MTOR, and TSC1) arise recurrently in ccRCC and are believed to cooperate with VHL inactivation to promote the development and evolution of ccRCC tumours8,9. This evidence concerns the gene PBRM1 and nonpapillary renal cell carcinoma.