von Hippel-Lindau (VHL) disease is a hereditary tumor syndrome predisposing to multifocal bilateral renal cell carcinomas (RCCs), pheochromocytomas, and pancreatic tumors, as well as angiomas and hemangioblastomas of the CNS. A candidate gene for VHL was recently identified, which led to the isolation of a partial cDNA clone with extended open reading frame, without significant homology to known genes or obvious functional motifs, except for an acidic pentamer repeat domain. To further characterize the functional domains of the VHL gene and assess its involvement in hereditary and nonhereditary tumors, we performed mutation 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 all (6/6) sporadic RCC cell lines analyzed showed mutations within the VHL gene. Both germ-line and somatic mutations included deletions, insertions, splice-site mutations, and missense and nonsense mutations, all of which clustered at the 3' end of the corresponding partial VHL cDNA open reading frame, including an alternatively spliced exon 123 nt in length, suggesting functionally important domains encoded by the VHL gene in this region. Over 180 sporadic tumors 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 of sporadic RCCs, acts as a recessive tumor-suppressor gene, and appears to encode important functional domains within the 3' end of the known open reading frame.

Three 3p probes were localized by in situ hybridization on chromosomes from a carrier of a balanced t(3;8) associated with renal cell cancer. For one of the probes (pH3E4/D3S48), a previous localization in 3p21 was confirmed; for a second probe (pHF12-32/D3S2), a broader localization could be confined to 3p21. Both probes appeared to be located distal to the breakpoint in 3p. The third probe (pMS1-37/D3S3) was localized to 3p14, in accordance with a previous localization. This probe, however, hybridized very weakly or not at all to either of the translocation products, although it is known from Southern analysis that the D3S3 sequence is present on one of them. We assume that this probe is located close to the breakpoint on 3p and that distortion of the higher-order chromosomal structure in this region is causing the failure of the in situ hybridization.

A 37-year-old woman with a history of bilateral mesenchymal cystic hamartomata of the lung was subsequently found to have low-grade endometrial stromal sarcoma. Cytogenetic analysis of the uterine tumor revealed, in all metaphases, an unusual derivative chromosome generated by the insertion of chromosome 19 into chromosome 10 at the level of its centromere [ins(10;19)(p11;p13q13)].