VHL and nonpapillary renal cell carcinoma: In fact, ongoing integrative molecular profiling efforts, focused on ccRCC pathophysiology, have highlighted the fact that ccRCC is much more than just the aberrant proliferation of renal cellularity, but rather a fundamentally metabolic disease, defined by specific key genetic mutations in target metabolic pathways, resulting in ccRCC metabolic reprogramming, throughout various cellular processes—cellular oxygenation (VHL), epigenetic modifications (PBRM1, SETD2, BAP1), and growth factor mediated intracellular signaling (MTOR).