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

Objectives-Cerebellar haemangioblastoma occurs sporadically or as a compone nt tumour of autosomal dominant von Hippel-Lindau disease. Biallelic inacti vation of the VHL tumour suppresser gene, which is located on chromosome 3p , has been shown to be involved in the pathogenesis of both tumour entities . mechanisms of I VHL inactivation are intragenic mutations, mitotic recomb ination events, and hypermethylation of the promoter region. The systematic and complete examination of these genetic and epigenetic phenomena in larg e series of van Hippel-Lindau disease related and sporadic hemangioblastoma s has, thus far, not been performed. Methods-In the largest series to date, 29 von Hippel-Lindau disease associa ted and 13 sporadic haemangioblastamas were investigated for ah suggested i nactivating mechanisms of the VNL gene using single strand conformational p olymorphism (SSCP), loss of heterozygosity (LOH), and methylation analyses. Additionally, corresponding blood samples of all patients were screened fo r VHL germline mutations by SSCP and Southern blotting. Results-Germline mutations were identified in 94% of patients with van Hipp el-Lindau disease and their tumours and 62% of these hemangioblastomas show ed LOPI of chromosome 3p. Of the 13 sporadic tumours, 23% showed a single s omatic mutation of the VHL gene chat was not present in the germtime. 3p LO H was identified in 50% of informative sporadic tumours. No ron Hippel-Lind au disease related or sporadic tumour demonstrated VHL promoter hypermethyl ation. Conclusions-For most vou Hippel-Lindau disease related haemangioblastomas, tire inactivation or loss of both alleles of the VHL gene, as predicted by the Knudson are hit theory, is required. However in a subset of tumours inc luding most sporadic haemangioblastomas, the genetic pathways involved in t umorigenesis have yet to be defined and may represent alterations of a diff erent pathway or pathways.