Abstract
Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome characterised by the development of retinal and central nervous system haemangioblastomas, renal cell carcinoma (RCC), phaeochromocytoma and pancreatic tumours. The VHL disease gene maps to chromosome 3p25-p26. To investigate the mechanism of tumourigenesis in VHL disease, we analysed 24 paired blood/tumour DNA samples from 20 VHL patients for allele loss on chromosome 3p and in the region of tumour suppressor genes on chromosomes 5, 11, 13, 17 and 22. Nine out of 24 tumours showed loss of heterozygosity (LOH) at at least one locus on chromosome 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 tumour types (RCC, haemangioblastoma, phaeochromocytoma and pancreatic tumour) suggesting a common mechanism of tumourigenesis in all types of tumour in VHL disease. The smallest region of overlap was between D3S1038 and D3S18, a region that corresponds to the target region for the VHL gene from genetic linkage studies. The parental origin of the chromosome 3p25-p26 allele loss could be determined in seven tumours from seven familial cases; in each tumour, the allele lost had been inherited from the unaffected parent. Our results suggest that the VHL disease gene functions as a recessive tumour suppressor gene and that inactivation of both alleles of the VHL gene is the critical event in the pathogenesis of VHL neoplasms. Four VHL tumours showed LOH on other chromosomes (5q21, 13q, 17q) indicating that homozygous VHL gene mutations may be required but may not be sufficient for tumourigenesis in VHL disease.
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Anglard P, Tory K, Brauch H, Weiss GH, Latif F, Merino MJ, Lerman MI, Zbar B, Linehan WM (1991) Molecular analysis of genetic changes in the origin and development of renal cell carcinoma. Cancer Res 51:1071–1077
Binkovitz LA, Johnson CD, Stephens DH (1990) Islet cell tumors in von Hippel-Lindau disease: increased prevalence and relationship to the multiple endocrine neoplasias. AJR Am J Roentgenol 155:501–505
Cohen AJ, Li FP, Berg S, et al. (1979) Hereditary renal cell carcinoma associated with a chromosomal translocation. N Engl J Med 301:592–595
Crossey PA, Maher ER, Jones MH, Richards FM, Latif F, Phipps ME, Lush M, Foster K, Tory K, Green JS, Oostra B, Yates JRW, Lineham WM, Affara NA, Lerman M, Zbar B, Nakamura Y, Ferguson-Smith MA (1993) Genetic linkage between von Hippel-Lindau disease and three microsatellite polymorphisms refines the localisation of the VHL locus. Hum Mol Genet 2:279–282
Decker HJ, Gemmill RM, Neumann HP, Walter TA, Sandberg AA (1989). Loss of heterozygosity on 3p in a renal cell carcinoma in von Hippel-Lindau syndrome. Cancer Genet Cytogenet 39: 289–293
Goodman MD, Goodman BK, Lubin MB, Braunstein G, Rotter JI, Schreck RR (1990) Cytogenetic characterization of renal cell carcinoma in von Hippel-Lindau syndrome. Cancer 65:1150–1154
Hosoe S, Brauch H, Latif F, Glenn G, Daniel L, Bale S, Choyke P, Gorin M, Oldfield E, Berman A, et al (1990) Localization of the von Hippel-Lindau disease gene to a small region of chromosome 3. Genomics 8:634–640
Jones MH, Nakamura Y (1992) Detection of loss of heterozygosity at the human TP53 locus using a dinucleotide repeat polymorphism. Genes Chromosom Cancer 5:89–90
Jones MH, Yamakawa K, Nakamura Y (1992) Isolation and characterisation of 19 dinucleotide repeat polymorphisms on chromosome 3p. Hum Mole Genet 1:131–133
Knudson AG (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68:820–823
Kovacs G, Kung HF (1991) Nonhomologous chromatid exchange in hereditary and sporadic renal cell carcinomas. Proc Natl Acad Sci USA 88:194–198
Latif F, Tory K, Gnarra J, Yao M, Duh F-M, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L, Schmidt L, Zhou F, Li H, Wei MH, Chen F, Glenn G, Choyke P, Walther MM, Weng Y, Duan DR, Dean M, Glavac D, Richards FM, Crossey PA, Ferguson-Smith MA, Le Paslier D, Chumakov I, Cohen D, Chinault CA, Mahler ER, Linehan WM, Zbar B, Lerman MI (1993) Isolation of the von Hippel-Lindau disease tumour suppressor gene. Science 260:1317–1320
Maher ER, Yates JR (1991) Familial renal cell carcinoma: clinical and molecular genetic aspects. Br J Cancer 63:176–179
Maher ER, Yates JR, Harries R, Benjamin C, Harris R, Moore AT, Ferguson-Smith MA (1990) Clinical features and natural history of von Hippel-Lindau disease. Q J Med 77:1151–1163
Maher ER, Bentley E, Yates JR, Barton D, Jennings A, Fellows IW, Ponder MA, Ponder BA, Benjamin C, Harris R, et al. (1990) Mapping of von Hippel-Lindau disease to chromosome 3p confirmed by genetic linkage analysis. J Neurol Sci 100:27–30
Maher ER, Yates JR, Ferguson-Smith MA (1990) Statistical analysis of the two state mutation model in von Hippel-Lindau disease, and in sporadic cerebellar haemangioblastoma and renal cell carcinoma. J Med Genet 27:311–314
Maher ER, Bentley E, Yates JR, Latif F, Lerman M, Zbar B, Affara NA, Ferguson-Smith MA (1991) Mapping of the von Hippel-Lindau disease locus to a small region of chromosome 3p by genetic linkage analysis. Genomics 10:957–960
Marineau C, Baron C, Delattre O, Zucman J, Thomas G, Rouleau GA (1993) Dinucleotide repeat polymorphism at the D22S268 locus. Hum Mol Genet 2:336
Morita R, Saito S, Ishikawa J, Ogawa O, Yoshida O, Yamakawa K, Nakamura Y (1991) Common regions of deletion on chromosomes 5q, 6q, and 10q in renal cell carcinoma. Cancer Res 51:5817–5820
Neumann HP, Dinkel E, Brambs H, Wimmer B, Friedburg H, Volk B, Sigmund G, Riegler P, Haag K, Schollmeyer P, et al (1991) Pancreatic lesions in the von Hippel-Lindau syndrome. Gastroenterology 101:465–471
Richards FM, Phipps ME, Latif F, Yao M, Crossey PA, Foster K, Linehan WM, Affara NA, Lerman MI, Zbar B, Ferguson-Smith ME, Maher ER (1993) Mapping the von Hippel-Lindau disease tumour suppressor gene: identification of germline deletions by pulsed field gel electrophoresis in two VHL disease patients. Hum Mol Genet 2:879–882
Seizinger BR, Rouleau GA, Ozelius LJ, Lane AH, Farmer GE, Lamiell JM, Haines J, Yuen JJW, Collins D, Majoor-Krakrauer D, et al (1988) Von Hippel-Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature 332:268–269
Seizinger BR, Smith DI, Filling-Katz MR, Neumann H, Green JS, Choyke PL, Anderson KM, Freiman RN, Klauck SM, Whaley J, et al (1991) Genetic flanking markers refine diagnostic criteria and provide insights into the genetics of Von Hippel Lindau disease. Proc Natl Acad Sci USA 88:2864–2868
Sharf SJ, Bowcock AM, McClure G, Klitz W, Yandell DW, Erlich HA (1992) Amplification and characterization of the retinoblastoma gene VNTR by PCR. Am J Hum Genet 50:371–381
Spirio L, Nelson L, Joslyn G, Leppert M, White R (1992) A CA repeat 30–70 kb downstream from the adenomatous polyposis coli (APC) gene. Nucleic Acids Res 20:642
Suzuki Y, Tamura G, Satodate R, Fujioka T (1992) Infrequent mutation of p53 gene in human renal cell carcinoma detected by polymerase chain reaction single-strand conformation polymorphism analysis. Jpn J Cancer Res 83:233–235
Tory K, Brauch H, Linehan M, Barba D, Oldfield E, Filling-Katz M, Seizinger B, Nakamura Y, White R, Marshall FF, et al (1989) Specific genetic change in tumors associated with von Hippel-Lindau disease. J Natl Cancer Inst 81:1097–1101
Tory K, Latif F, Modi W, Schmidt L, Wei MH, Li H, et al. (1992) A genetic map of 96 loci on the short arm of human chromosome 3. Genomics 13:275–286
Yamakawa K, Morita R, Takahashi E, Hori T, Ishikawa J, Nakamura Y (1991) Detailed deletion mapping of the short arm of chromosome 3 in sporadic renal cell carcinoma. Cancer Res 51:4707–4711
Yamakawa K, Takahashi E, Murata M, Okui K, Yokoyama S, Nakamura Y (1992) Detailed mapping around the breakpoint of (3; 8) translocation in familial renal cell carcinoma and FRA3B. Genomics 14:412–416
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Crossey, P.A., Foster, K., Richards, F.M. et al. Molecular genetic investigations of the mechanism of tumourigenesis in von Hippel-Lindau disease: analysis of allele loss in VHL tumours. Hum Genet 93, 53–58 (1994). https://doi.org/10.1007/BF00218913
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DOI: https://doi.org/10.1007/BF00218913