Since our current and previous mouse genetic studies collectively show that the requirement for HIF-1α and HIF-2α is dependent on the underlying genotype of the tumour (Vhl/Trp53 mutations versus Vhl/Trp53/Rb1 mutations), it will be important to test the generality of our findings in other genetic mouse models of ccRCC, particularly as epigenetic modifications resulting from mutations in Pbrm1 have been shown to alter HIF-α transcriptional outputs12,64,65. The gene discussed is EPAS1; the disease is nonpapillary renal cell carcinoma.