Our study reports for the first time the epigenetic modulation of KEAP1 by CpGs promoter hypermethylation as the leading mechanism of KEAP1 deregulation in ccRCC and together with recently published data on PRCC2, corroborate the hypothesis of a driver role of the Keap1/Nrf2 pathway in the ccRCCs subtypes with a specific epigenetic deregulation mechanism. This evidence concerns the gene KEAP1 and nonpapillary renal cell carcinoma.