Purpose: Members of a family carrying a constitutional balanced translocation [t(3;8) (p14;q24)] have a high risk of developing multiple, bilateral clear-cell renal carcinomas. Two genetic mechanisms of carcinogenesis for this malignancy have been proposed: (1) disruption of a gene at the translocation breakpoint and (2) mutation of the von Hippel-Lindau tumor-suppressor gene at 3p25. This study further evaluates the role of the von Hippel-Lindau gene in the etiology and pathogenesis of t(3;8)-associated renal carcinomas.
Methods: Two new t(3;8)-associated renal carcinomas were tested for mutations in the von Hippel-Lindau gene by single-stranded conformational polymorphism analysis followed by direct DNA sequencing, for loss of alleles on chromosomes 3p and 8, and for methylation abnormalities in the first cloned exon of the von Hippel-Lindau gene.
Results: A missense mutation in the von Hippel-Lindau gene was found in one of the two t(3;8)-associated renal carcinomas. This mutation would produce a stop codon and a truncated protein. Both tumors showed a loss of alleles on the derivative 8 chromosome. When these results were combined with the results of our previous studies, two of the four t(3;8)-associated renal carcinomas, which were examined for molecular genetic changes, showed different von Hippel-Lindau somatic mutations. All renal tumors from the 3;8 translocation family showed loss of the translocated portion of chromosome 3.
Conclusions: These results support a mechanism of tumorigenesis in the chromosome (3;8) translocation family that involves the loss of both copies of the von Hippel-Lindau gene.