GERM-LINE MUTATIONS IN THE VON HIPPEL-LINDAU TUMOR-SUPPRESSOR GENE ARE SIMILAR TO SOMATIC VON HIPPEL-LINDAU ABERRATIONS IN SPORADIC RENAL-CELL CARCINOMA

von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome predisp osing to multifocal bilateral renal. cell carcinomas (RCCs), pheochrom ocytomas, and pancreatic tumors, as well as angiomas and hemangioblast omas of the CNS. A candidate gene for VHL was recently identified, whi ch led to the isolation of a partial cDNA clone with extended open rea ding frame, without significant homology to known genes or obvious fun ctional motifs, except for an acidic pentamer repeat domain. To furthe r characterize the functional domains of the VHL gene and assess its i nvolvement in hereditary and nonhereditary tumors, we performed mutati on analyses and studied its expression in normal and tumor tissue. We identified germline mutations in 39% of VHL disease families. Moreover , 33% of sporadic RCCs and ah (6/6) sporadic RCC cell lines analyzed s howed mutations within the VHL gene. Both germ-line and somatic mutati ons included deletions, insertions, splice-site mutations, and missens e and nonsense mutations, all of which clustered at the 3' end of the corresponding partial VHL cDNA open reading frame, including an altern atively spliced exon 123 nt in length, suggesting functionally importa nt domains encoded by the VHL gene in this region. Over 180 sporadic t umors of other types have shown no detectable base changes within the presumed coding sequence of the VHL gene to date. We conclude that the gene causing VHL has an important and specific role in the etiology o f sporadic RCCs, acts as a recessive tumor-suppressor gene, and appear s to encode important functional domains within the 3' end of the know n open reading frame.