**11. Conclusions**

Inactivation of the VHL tumor suppressor gene is the hallmark of clear cell renal cancer and leads to the upregulation of wide-spread hypoxia pathways, orchestrated by the transcription factor HIF. Whilst HIF proteins activate many genes that are central to the "hallmarks of cancer", other HIF-target genes may restrict cancer progression and the overall consequence of HIF pathway activation is a balance of these effects (**Figure 4**). Both genetic and epigenetic genetic events, occurring before or after VHL loss and HIF activation, can alter this balance to promote tumorigenesis.
