VHL and nonpapillary renal cell carcinoma: That there is such pressure to modulate the output of HIF system at an early stage in ccRCC development is consistent first with evidence that VHL-inactivation itself (and hence general un-physiological up-regulation of HIF) is an early event in ccRCC development [12–14], and secondly with the existence of changes in HIF-α isoform expression associated with ccRCC development [16,18].