To ascertain the relevance of these observations within differentiated renal tubular epithelia (the presumed cell of origin of human ccRCC)27–29, we sought to generate genetically engineered mice with renal tubular specific deletion of Vhl, Pbrm1 or both Vhl and Pbrm1. We have previously described the development of Pax8CreERT2 transgenic mice16 that allow highly specific and inducible targeting of all renal tubular compartments (proximal, distal tubules and collecting ducts). Here, PBRM1 is linked to nonpapillary renal cell carcinoma.