VHL and nonpapillary renal cell carcinoma: Many efforts have characterized the genomic landscape of ccRCC, revealing important driver events such as biallelic inactivation of VHL, followed by mutations in chromatin remodeling and histone modification related genes PBRM1, BAP1, and SETD2. 2,3,4,5,6 Intra-tumoral heterogeneity (ITH) of these subsequent mutational events appears to be a salient feature of ccRCC, as revealed by previous multi-region exome sequencing studies.5