CcRCC differs from many tumor types in that it is characterized by frequent mutation of epigenetic regulators (dominated by SETD2 (10-15%), PBRM1 (33-45%), and BAP1 (15%)), while mutations in other common cancer gene pathways (e.g. RAS, BRAF, TP53, RB) are largely absent [2-5], and ccRCC is tightly linked to a distinct transcriptional signature due to inactivation of the VHL gene, which is mediated in part through deregulation of the epigenome [6]. The gene discussed is SETD2; the disease is nonpapillary renal cell carcinoma.