Reconsideration of biallelic inactivation of the VHL tumour suppressor gene in hemangioblastomas of the central nervous system

Abstract

Objectives-Cerebellar haemangioblastoma occurs sporadically or as a component tumour of autosomal dominant von Hippel-Lindau disease. Biallelic inactivation of the VHL tumour suppressor gene, which is located on chromosome 3p, has been shown to be involved in the pathogenesis of both tumour entities. Mechanisms of VHL inactivation are intragenic mutations, mitotic recombination events, and hypermethylation of the promoter region. The systematic and complete examination of these genetic and epigenetic phenomena in large series of von Hippel-Lindau disease related and sporadic hemangioblastomas has, thus far, not been performed. Methods-In the largest series to date, 29 von Hippel-Lindau disease associated and 13 sporadic haemangioblastomas were investigated for all suggested inactivating mechanisms of the VHL gene using single strand conformational polymorphism (SSCP), loss of heterozygosity (LOH), and methylation analyses. Additionally, corresponding blood samples of all patients were screened for VHL germline mutations by SSCP and Southern blotting. Results-Germline mutations were identified in 94% of patients with von HippelLindau disease and their tumours and 62% of these hemangioblastomas showed LOH of chromosome 3p. Of the 13 sporadic tumours, 23% showed a single somatic mutation of the VHL gene that was not present in the germline. 3p LOH was identified in 50% of informative sporadic tumours. No von Hippel-Lindau disease related or sporadic tumour demonstrated VHL promoter hypermethylation. Conclusions-For most von Hippel-Lindau disease related haemangioblastomas, the inactivation or loss of both alleles of the VHL gene, as predicted by the Knudson two hit theory, is required. However, in a subset of tumours including most sporadic haemangioblastomas, the genetic pathways involved in tumorigenesis have yet to be defined and may represent alterations of a diVerent pathway or pathways. (J Neurol Neurosurg Psychiatry 2001;70:644-648)

Calculating optimal surveillance for detection of von Hippel–Lindau-related manifestations

“…The young age of pheochromocytoma onset indicates the oncogenic dominant function of the VHL gene (Hes et al 2003). Causes of LOH of the VHL gene can be either mutation or methylation of the second allele (Crossey et al 1994, Herman et al 1994, Prowse et al 1997, Glasker et al 2001, Kim & Kaelin 2004. Moreover, recent studies have shown that mutations or methylation of other vulnerable (flanking) genes also affect the VHL phenotype (Martinez et al 2000, Gijtenbeek et al 2002.…”

Genetic analysis of von Hippel-Lindau disease

“…Somatic VHL mutations are commonly involved in the tumorigenesis of hemangioblastomas, accounting for up to 50% of sporadic retinal and CNS hemangioblastomas [Maher et al, 1990a;Neumann et al, 1989;Oberstrass et al, 1996;Richard et al, 1998]. Interestingly, sporadic pheochromocytoma are rarely (3%) due to somatic VHL mutations [Bar et al, 1997;Eng et al, 1995;Glasker et al, 2001;Neumann et al, 1993;Sprenger et al, 2001]. However, up to 25% of seemingly sporadic pheochromocytomas actually have a germline VHL, NF-1, c-RET, or SDH mutations.…”

Risk of new tumors in von Hippel–Lindau patients depends on age and genotype

“…In line with Knudson's two-hit hypothesis, tumor development requires both an inherited VHL germline mutation in one allele (first hit), present in all the patient's cells, and a somatic loss or inactivation of the wild-type allele (second hit). 31 However, studies of second hit in vHL lesions have so far been based on only a small number of tumors, [32][33][34][35][36] and further studies are needed to elucidate the role the second hit in tumor development.…”