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Von Hippel–Lindau (VHL) disease is an autosomal dominant hereditary cancer syndrome with a prevalence of 1 in 39,000 live births that results from a germline mutation of the VHL gene with over 90% penetrance by 65 years of age despite variable expression [1, 2]. VHL is a tumor suppressor gene located on the short arm of the chromosome 3 (3p25–26) that is made of three exons and widely expressed in both fetal and adult tissues [3, 4]. A patient with heritable VHL disease inherits a germline mutation of the gene from the affected parent and a normal gene from the unaffected parent (wild type). The Knudson’s two-hit hypothesis of tumorigenesis applies to the initiation of the tumor growth when a somatic mutation affects the wildtype VHL allele [5]. Although germline VHL mutations are present in all the cells of the affected individuals who inherit the genetic trait, only the cells that are somatically mutated in the wild-type gene and are parts of a susceptible organ experience tumor growth [2]. In fact, patients with VHL disease are predisposed to develop specific central nervous system (CNS) and visceral lesions [1, 2, 4]. Affected individuals may develop retinal hemangioblastomas, endolymphatic sac tumors (ELST) of the labyrinth, or craniospinal hemangioblastomas in the cerebellum, brainstem, or spinal cord [2]. Furthermore, visceral involvement in some patients affects the kidney with renal cell carcinoma (RCC) or cysts, the adrenal glands with pheochromocytomas, the pancreas with tumors or cysts, and the epididymus or the broad ligament with cystoadenomas [2]. Clinical criteria or genetic tests help in diagnosing VHL disease [1]. Obviously, patients with a family history of VHL and CNS lesions (hemangioblastomas), RCC, pheochromocytoma, pancreatic cysts or ELST will meet the criteria for diagnosis of VHL [1]. However, 20% of patients lack a family history, but meet the criteria for VHL, if they present two or more CNS hemangioblastomas, or one CNS hemangioblastoma and a visceral VHL-associated tumor [1]. A classification of the VHL disease in type 1 or 2A–C based on the VHL mutation, molecular defect, and clinical manifestations have been proposed [4]. Patients at high risk undergo testing for germline VHL mutations with 100% detection rate if they have a positive family history [1, 6]. On the contrary, patients with negative family history present with tissue mosaicism that may hamper the use of testing their peripheral blood leukocytes lacking the VHL mutation [7]. The somatic VHL mutations are present in approximately 50% of sporadic RCC, whereas 20% of cases present hypermethylated VHL gene in the same group of tumors [4]. Hypermethylation of the VHL gene has only been described in the RCC, while somatic mutations account for 30% of sporadic hemangioblastomas without any description of VHL gene hypermethylation in this group of tumors [4]. In the context of sporadic tumors, the two-hit model occurs exclusively somatically rather than in the germline [4]. The VHL gene is widely expressed in tissues, including the ones not affected by VHL-transformed phenotype. The VHL mRNA encodes a 213 amino acid residue-protein (pVHL) with an apparent molecular weight of ~24 to 30 kDa (VHL30) [1, 4]. A second pVHL isoform of approximately 19 kDa (VHL19) is the by-product of inframe start codon (ATG) at codon 54 [4]. Both isoforms have tumor suppressor activity. pVHL shuttles between the nucleus and the cytoplasm, and the nuclear-cytoplasmic trafficking is required for the function of the VHL tumor suppressor protein [4]. Primarily, pVHL complexes with J Mol Med (2009) 87:591–593 DOI 10.1007/s00109-009-0466-z

Beyond the Knudson’s hypothesis in von Hippel–Lindau (VHL) disease—proposing vitronectin as a “gene modifier”