ccRCC is most often associated with a mutation in the VHL (von Hippel–Lindau) gene, which encodes an E3 ubiquitin ligase, either as a point mutation or as part of a large deletion of chromosomal arm 3p. This chromosomal arm contains BAF180, BAF155, the Set domain–containing protein 2 (SetD2, a H3K36 methyltransferase), and the BAP1 tumor suppressor, which is a deubiquitinase. Thus, a large number of tumor suppressors reside in this region. However, it appears that missense mutation of either VHL, BAP1, or BAF180 can contribute to ccRCC independently, suggesting an interesting interplay of these genes in the pathogenesis of this tumor. Mutations in PBRM1 correlate with mutations in VHL, the most commonly mutated gene in ccRCC, and have a tendency toward mutual exclusivity with BAP1 mutations (93). Somewhat surprisingly, the other subunits of the pBAF complex are not mutated with high frequency in ccRCC.
