MOLECULAR-GENETIC INVESTIGATIONS OF THE MECHANISM OF TUMORIGENESIS INVON HIPPEL-LINDAU DISEASE - ANALYSIS OF ALLELE LOSS IN VHL TUMORS

Von Hippel-Lindau (VHL) disease is a dominantly inherited familial can cer syndrome characterised by the development of retinal and central n ervous system haemangioblastomas, renal cell carcinoma (RCC), phaeochr omocytoma and pancreatic tumours. The VHL disease gene maps to chromos ome 3p25-p26. To investigate the mechanism of tumourigenesis in VHL di sease, we analysed 24 paired blood/tumour DNA samples from 20 VHL pati ents for allele loss on chromosome 3p and in the region of tumour supp ressor genes on chromosomes 5, 11, 13, 17 and 22. Nine out of 24 tumou rs showed loss of heterozygosity (LOH) at at least one locus on chromo some 3p and in each case the LOH included the region to which the VHL gene has been mapped. Chromosome 3p allele loss was found in four tumo ur types (RCC, haemangioblastoma, phaeochromocytoma and pancreatic tum our) suggesting a common mechanism of tumourigenesis in all types of t umour in VHL disease. The smallest region of overlap was between D3S10 38 and D3S18, a region that corresponds to the target region for the V HL gene from genetic linkage studies. The parental origin of the chrom osome 3p25-p26 allele loss could be determined in seven tumours from s even familial cases; in each tumour, the allele lost had been inherite d from the unaffected parent. Our results suggest that the VHL disease gene functions as a recessive tumour suppressor gene and that inactiv ation of both alleles of the VHL gene is the critical event in the pat hogenesis of VHL neoplasms. Four VHL tumours showed LOH on other chrom osomes (5q21, 13q, 17q) indicating that homozygous VHL gene mutations may be required but may not be sufficient for tumourigenesis in VHL di sease.