Molecular genetic investigations of the mechanism of tumourigenesis in von Hippel-Lindau disease: analysis of allele loss in VHL tumours

Abstract

Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome characterised by the development of retinal and central nervous system haemangioblastomas, renal cell carcinoma (RCC), phaeochromocytoma and pancreatic tumours. The VHL disease gene maps to chromosome 3p25-p26. To investigate the mechanism of tumourigenesis in VHL disease, we analysed 24 paired blood/tumour DNA samples from 20 VHL patients for allele loss on chromosome 3p and in the region of tumour suppressor genes on chromosomes 5, 11, 13, 17 and 22. Nine out of 24 tumours showed loss of heterozygosity (LOH) at at least one locus on chromosome 3p and in each case the LOH included the region to which the VHL gene has been mapped. Chromosome 3p allele loss was found in four tumour types (RCC, haemangioblastoma, phaeochromocytoma and pancreatic tumour) suggesting a common mechanism of tumourigenesis in all types of tumour in VHL disease. The smallest region of overlap was between D3S1038 and D3S18, a region that corresponds to the target region for the VHL gene from genetic linkage studies. The parental origin of the chromosome 3p25-p26 allele loss could be determined in seven tumours from seven familial cases; in each tumour, the allele lost had been inherited from the unaffected parent. Our results suggest that the VHL disease gene functions as a recessive tumour suppressor gene and that inactivation of both alleles of the VHL gene is the critical event in the pathogenesis of VHL neoplasms. Four VHL tumours showed LOH on other chromosomes (5q21, 13q, 17q) indicating that homozygous VHL gene mutations may be required but may not be sufficient for tumourigenesis in VHL disease.

Genetic analysis of von Hippel-Lindau disease

“…Initially it was noted that phenotypes in Caucasian VHL families paralleled Japanese families for most mutations . Later studies by Yoshida et al [2000] found that mutations p.Arg113Ter, p.Gln132Ter, p.Leu158Val, and p.Cys162Tyr, which were previously associated with VHL Type 1 in Western cultures [Crossey et al, 1994a;Glavac et al, 1996;Maher et al, 1996;Zbar et al, 1996], were associated with VHL Type 2 in Japanese families [Clinical Research Group for VHL in Japan, 1995;Yoshida et al, 2000]. A study of 15 Korean patients showed the majority of VHL Type 1 mutations were nonmissense mutations, similar to those found in Japan and Western cultures [Cho et al, 2009].…”

Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas

“…VHL is considered a classical tumor suppressor gene in the sense that, in accordance with Knudsons two-hit model, biallelic inactivation is usually required for tumorigenesis (Knudson 1971(Knudson , 1996. Loss of heterozygosity (LOH) of the wild-type allele is frequent in VHL-associated tumors, including PCCs (Crossey et al 1994), and hypermethylation of the wild-type allele as an alternative mechanism of gene inactivation has also been reported (Herman et al 1994, Prowse et al 1997, although not in PCCs (Bender et al 2000). Disease-causing mutations in VHL can be missense, nonsense, as well as deletions and insertions (indels), with missense mutations being more frequent in families with PCC/PGL (Woodward & Maher 2006).…”

The von Hippel-Lindau Gene Product Inhibits Vascular Permeability Factor/Vascular Endothelial Growth Factor Expression in Renal Cell Carcinoma by Blocking Protein Kinase C Pathways

“…Germ line mutations or loss of the von Hippel-Lindau (VHL) 1 gene predispose to a rare hereditary cancer syndrome characterized by the development of renal cell carcinoma (RCC) as well as other tumors including central nervous system hemangioblastomas, pheochromocytomas, and retinal angiomas (1)(2)(3)(4)(5)(6)(7)(8). The VHL gene, which maps to chromosome 3p25-p26, is also commonly mutated or silenced in sporadic RCC and, like p53 and Rb, fulfills Knudsen's criteria for a tumor suppressor gene (5,6,9,10).…”