However,VHL mutations alone are insufficient to drive disease progression, and have no prognostic or predictive value.13,14 Mounting evidence has revealed an emerging role of other genes, heavily involved in chromatin rearrangement and epigenetic DNA modifications, includingPBRM1, SETD2, BAP1, andKDM5C in ccRCC progression.15,16 Inactivating mutations or/and low expression of these genes in primary renal tumors have been associated with poor outcomes.17,23. This evidence concerns the gene VHL and nonpapillary renal cell carcinoma.