Molecular genetic analysis of the von Hippel-Lindau disease tumor suppressor gene in familial and sporadic cerebellar hemangioblastomas.

Cerebellar hemangioblastoma is one of the most frequent manifestations of the autosomal dominantly inherited von Hippel-Lindau (VHL) disease but also may manifest as a sporadic tumor. The purpose of this study was to define the alterations of the VHL gene in hemangioblastomas. We analyzed nine specimens from eight cerebellar hemangioblastomas (three familial and five sporadic) and six blood samples from family members of two unrelated pedigrees for mutations of the VHL gene using single-strand conformation polymorphism analysis and direct sequencing. We identified germline mutations in all VHL-associated tumors and somatic mutations in two (40%) of five sporadic hemangioblastomas. We also observed germline mutations in the peripheral blood DNA from members of two unrelated families; one is currently without VHL manifestations, and the other is affected. In addition, loss of heterozygosity of allelic markers on chromosome 3p were examined by four polymorphic microsatellite markers, and aberrant methylation of the VHL gene was investigated with a methylation-sensitive enzyme, Sma I. Allelic losses on chromosome 3p were observed from two patients with VHL disease in one family and in one of two sporadic hemangioblastomas. No hypermethylation of the VHL gene was detected in any of the tumors that we examined. Our findings suggest that the VHL tumor suppressor gene is the target for inactivation in this tumor and is involved in the pathogenesis of familial and sporadic hemangioblastomas.