In both, sporadic and hereditary ccRCC, VHL inactivation results in the stabilization of hypoxia inducible factors, HIF-1α and HIF-2α, and activation of hypoxia-response signaling pathways that, in certain tissues, promote tumor development (Gossage et al. 2015, Kaelin 2022). This evidence concerns the gene EPAS1 and nonpapillary renal cell carcinoma.