VHL and renal cell carcinoma: The most dramatic example of O2-independent HIF-1α and HIF-2α protein expression occurs in tumors associated with the von Hippel-Lindau syndrome, in which affected individuals are heterozygous for a germline loss-of-function mutation in the VHL tumor suppressor gene and the other allele is inactivated in the tumor tissue, leading to development of the clear-cell type of renal cell carcinoma (RCC), central nervous system and retinal hemangioblastoma, pancreatic neuroendocrine tumor, and other neoplasms (26).