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 ofVHL 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 theVHL 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 Hippel-Lindau 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 theVHL 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 VHLpromoter hypermethylation.

CONCLUSIONS For most von Hippel-Lindau disease related haemangioblastomas, the inactivation or loss of both alleles of theVHL 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 different pathway or pathways.