VHL and nonpapillary renal cell carcinoma: In sporadic ccRCC, the first genetic event is often the haploid 3p loss that generates heterozygous loss of VHL, SETD2, PBRM1, and BAP1. The TICs then emerge after the loss of the second VHL allele, usually as a result of deletion, loss-of-function mutation, or epigenetic inactivation of gene expression.