In summary, these findings show the transcriptional up-regulation of HERV-E in ccRCC appears to be related to three critical events: (i) VHL inactivation, (ii) HIF-2α overexpression, and (iii) hypomethylation of the HERV-E 5′LTR (Figure 1). Here, VHL is linked to nonpapillary renal cell carcinoma.