The von Hippel-Lindau tumour suppressor protein (pVHL) is broadly inactivated (∼80%) in sporadic ccRCC by either mutation or promoter hypermethylation3, 7 and its tumour suppressor activity is dependent on its downregulation of the alpha subunits of the hypoxia-inducible factor (HIFα) family of transcription factors and in particular HIF2α (refs 8, 9, 10, 11). The gene discussed is EPAS1; the disease is nonpapillary renal cell carcinoma.