VHL and metastatic neoplasm: We performed unsupervised hierarchical clustering of major ccRCC driver mutations (with mutation frequency > 10% across TCGA KIRC cohort and TRACERx Renal [15]) that were previously shown to be associated with ITH [15] (i.e., VHL, PBRM1, SETD2, BAP1) and genomic alterations enriched with metastatic disease and ICI response (HLA LOH and CDKN2A/B copy number loss) [38, 44, 48], ultimately identifying two clusters (Fig. 3B, Additional file 1: Table S4).