Pancreatic Involvement in Von Hippel-Lindau Disease

Abstract

Von Hippel-Lindau (VHL) disease is characterized by a dominant autosomal predisposition to develop hemangioblastomas of the retina and central nervous system (CNS), renal cell carcinoma, pheochromocytoma and endolymphatic sac tumors with marked phenotypic variability.^1,2 The VHL gene, located on chromosome 3p25–26, is composed of three exons, encoding for a 213 amino acid protein which is widely expressed in both fetal and adult human tissues. A hallmark of VHL tumours is their high degree of vascularization, which arises from overexpression of the vascular endothelial growth factor (VEGF), a crucial factor in angiogenesis.² The VHL gene is a multifunctional tumour suppressor gene which is principally involved in negative regulation of hypoxia-inducible mRNAs such as the mRNA encoding for VEGF. The activity of VHL protein has been linked to the targeting of specific proteins for ubiquitin-dependent proteolysis.^1,2 Lack of degradation of this factor due to absence of the VHL protein results in uncontrolled production of factors promoting formation of blood vessels such as VEGF.² Reintroduction of wild-type VHL protein in renal cell carcinoma cell lines lacking wild-type VHL protein suppresses their high level of VEGF mRNA accumulation. In addition, reintroduction of wild-type VHL protein prevents the development of tumours in nude mouse xenografts, confirming the tumour suppressive function the VHL gene. Germ-line mutations in the VHL gene are extremely heterogeneous and are distributed widely throughout the coding sequence.^1–3