While all ccRCC in the Vhl∆/∆Trp53∆/∆Rb1∆/∆ background showed strong phospho-4E-BP1-staining, indicative of PI3K/mTOR-pathway activation, only 50% of the Vhl∆/∆Trp53∆/∆Rb1∆/∆Hif1a∆/∆ and 88% of the Vhl∆/∆Trp53∆/∆Rb1∆/∆Hif2a∆/∆ tumours were positive (Fig. 1d). This evidence concerns the gene PIK3CA and nonpapillary renal cell carcinoma.