There are geographic differences in the incidence such that the disease is rare in Japan compared with the Western world. There is a familial incidence of this disease in 2% of cases and the most importantly recognised is the association with von Hippel Lindau syndrome.Von Hippel Lindau syndrome is a disease inherited as an autosomal dominant but actually caused by the inheritance of a tumour suppressor gene (VHL); the syndrome comprises clinically: retinal angiomas, haemangioblastomas of the central nervous system, phaeochromocytomas and renal cell carcinoma of the clear cell type. What has caught the focus of the oncology community in recent years is the fact that the VHL gene seems to be responsible not only for the development of renal cell carcinoma in the VHL syndrome, but also that in 60% or more of the sporadic population of sufferers of clear cell renal cancer.
VHL protein (the product of the gene) functions as a tumour suppressor, inhibiting growth when introduced into cultures of renal cell carcinoma cells in vitro. Hypoxia inducible factor (HIF) and genes are normally inhibited by by VHL protein, including several involved in angiogenesis (e.g. vascular endothelial growth factor: VEGF), cell growth (e.g. transforming growth factor alpha: TGFa)etc. When VHL protein is lost these proteins are over-expressed leading to a micro-environment favourable for cancer growth. This is thought currently to be the major oncogenic pathway leading to renal cancer. Distinct from the von Hippel Lindau syndrome, familial clear cell renal cancer has been reported in patients with translocations of chromosome 3p at a fragile 3p14 locus, but there may well be a common pathway through the VHL protein to oncogenesis.
