VHL and nonpapillary renal cell carcinoma: Early studies indicated that the majority of ccRCC were associated with a loss of the von Hippel–Lindau (VHL) gene with induction of hypoxia-inducible factors (HIF) and vascular endothelium growth factors (VEGF)3, 4, and anti-VEGF targeted therapy remains the first-line treatment for metastatic ccRCC.