Abstract
von Hippel-Lindau (VHL) disease is a pleioropic disorder featuring a variety of malignant and benign tumors of the eye, central nervous system, kidney, and adrenal gland. Recently the VHL gene has been identified in the chromosomal region 3p25-26. Prognosis and successful management of VHL patients and their descendants depend on unambiguous diagnosis. Due to recurrent hemangioblastomas, a 29-year-old patient without familial history of VHL disease was diagnosed to be at risk for the disease. Histopathological examination of a small renal mass identified a clear cell tumor with a G1 grading. Genetic characterization of the germline and of the renal tumor was performed. Polymerase chain reaction/single strand conformation polymorphism (PCR/SSCP) analysis with primers from the VHL gene identified a deletion of a single nucleotide in exon 2 in the patient's germline and in the tumor, but not in the DNA of his parents. This deletion therefore must be a de novo mutation. Comparative genome hybridization (CGH) and fluorescence in situ hybridization (FISH) analysis of the G1 tumor with differentially labelled yeast artifical chromosome (YAC) clones showed loss of 3p and of the 3p26 signals, respectively. In conclusion, we identified a de novo germline mutation in the VHL gene of a young patient and a somatic chromosome 3p loss at the homologous chromosome 3 in his renal tumor. Our results suggest a recessive mode of inactivation of the VHL gene, providing solid evidence for its tumor-suppressor gene characteristics. Our data show the diagnostic potential of genetic testing, especially in patients without VHL family history. Furthermore, the findings of homozygous inactivation of the VHL gene in a G1 tumor support the notion that the inactivation of the VHL gene is an early event in tumorigenesis of renal cell carcinoma.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Cavenee WK, Dryja TP, Phillips RA, Benedict WF, Godbout R, Gallie BL, Murphee AL, Strong LC, White RL (1983) Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305: 779–784
Choyke PL, Glenn GW, Patronas NJ, Linehan WM, Zbar B (1995) Von Hippel-Lindau disease: genetic, clinical, and imaging features. Radiology 194: 629–642
Crossey PA, Foster K, Richards FM, Phipps ME, Latif F, Tory K, Jones MH, Bentley E, Kumar R, Lerman MI et al (1994a) 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
Crossey PA, Richards FM, Foster K, Green JS, Prowse A, Latif F, Lerman M, Zbar B, Affara NA, Ferguson-Smith MA, Maher ER (1994b) Identification of intragenic mutations in the von Hippel-Lindau disease tumor suppressor gene and correlation with disease phenotype. Hum Mol Genet 3: 1303–1308
Davies DR, Norman AM, Whitehouse RW, Evans DG (1994) Non-expression of von Hippel-Lindau phenotype in an obligate gene carrier. Clin Genet 45: 104–106
Decker HJ, Neumann HP, Walter TA, Sandberg AA (1988) 3p involvement in a renal cell carcinoma in von Hippel-Lindau syndrome. Region of tumor breakpoint clustering on 3p. Cancer Genet Cytogenet 33: 59–65
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
Decker HJ, Cannizzaro LA, Mendez MJ, Leong SP, Bixenman H, Berger C, Sandberg AA (1990) Chromosomes 17 and 22 involved in marker formation in neurofibrosarcoma in von Recklinghausen disease. A cytogenetic and in situ hybridization study. Hum Genet 85: 337–342
Decker HJ, Klauck SM, Lawrence JB, McNeil J, Smith D, Gemmill RM, Sandberg AA, Neumann HH, Simon B, Green J, et al (1994) Cytogenetic and fluorescence in situ hybridization studies on sporadic and hereditary tumors associated with von HippelLindau syndrome (VHL). Cancer Genet Cytogenet 77: 1- 13
Foster K, Crossey PA, Cairns P, Hetherington JW, Richards FM, Jones MH, Bentley E, Affara NA, Ferguson-Smith MA, Maher ER (1994a) Molecular genetic investigation of sporadic renal cell carcinoma: analysis of allele loss on chromosomes 3p, 5q, 1lp, 17 and 22. Br J Cancer 69: 230–234
Foster K, Prowse A, Berg A van den, Fleming S, Hulsbeek MM, Crossey PA, Richards FM, Cairns P, Affara NA, Ferguson-Smith MA, Buys CHCM, Maher ER (1994b) Somatic mutations of the von Hippel-Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma. Hum Mol Genet 3: 2169–2173
Glenn GM, Daniel LN, Choyke P, Linehan WM, Oldfield E, Gorin MB, Hosoe S, Latif F, Weiss G, Walther M et al (1991) Von Hippel-Lindau (VHL) disease: distinct phenotypes suggest more than one mutant allele at the VHL locus. Hum Genet 87: 207–210
Glenn GM, Linehan WM, Hosoe S, Latif F, Yao M, Choyke P, Gorin MB, Chew E, Olfield E, Manolatos C et al (1992) Screening for von Hippel-Lindau disease by DNA polymorphism analysis. J Am Med Assoc 267: 1226–1231
Gnarra JR, Tory K, Weng Y, Schmidt L, Wei MH, Li H, Latif F, Liu S, Chen F, Duh FM, Lubensky I, Duan DR, Florence C, Pozzatti R, Walther MM, Bander NH, Grossman HB, Brauch H, Pomer S, Brooks JD, Isaacs WB, Lerman MI, Zbar B, Linehan WM (1994) Mutations of the VHL tumor suppressor gene in renal carcinoma. Nat Genet 7: 85–89
Horton WA, Wong V, Eldrigde R (1976) Von Hippel-Lindau disease. Clinical and pathological manifestations in nine families with 50 affected members. Arch Intern Med 136: 769–777
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
Kallioniemi A, Kallioniemi OP, Sudar D, Rutovitz D, Gray JW, Waldman F, Pinkel D (1992) Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science 258: 818–821
Kanno H, Kondo K, Ito S, Yamamoto I, Fujii S, Torigoe S, Sakai N, Hosaka M, Shuin T, Yao M (1994) Somatic mutations of the von Hippel-Lindau tumor suppressor gene in sporadic central nervous system hemangioblastomas. Cancer Res 54: 4845–4847
Knudson AG Jr (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 carinomas. Proc Natl Acad Sci USA 88: 194–198
Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML, Stackhouse T, Kuzmin I, Modi W, Geil L et al (1993) Identification of the von Hippel-Lindau disease tumor suppressor gene [see comments]. Science 260: 1317–1320
Lengauer C, Riethman HC, Speicher M, Taniwaki M, Konecki D, Green ED, Becher R, Olson M, Cremer T (1992) Metaphase and interphase cytogenetics with Alu-PCR-amplified yeast artificial chromosome clones containing the BCR gene and the protooncogenes c-raf-1, c-fms, and c-erbB-2. Cancer Res 52: 2590–2596
Maher ER (1993) Von Hippel-Lindau disease. In: Hodgson SV, Maher ER (eds) A practical guide to human cancer genetics. Cambridge University Press, Cambridge, pp 157–162
Maher ER, Bentley E, Yates JR, Latif F, Lerman M, Zbar B, Affara NA, Ferguson-Smith MA (1991a) Mapping of the von Hippel-Lindau disease locus to a small region of chromosome 3p by genetic linkage analysis. Genomics 10: 957–960
Maher ER, Iselius L, Yates JR, Littler M, Benjamin C, Harris R, Sampson J, Williams A, Ferguson-Smith MA, Morton N (1991b) Von Hippel-Lindau disease: a genetic study. J Med Genet 28: 443–447
Manoir S du, Speicher MR, Joos S, Schrock E, Popp S, Dohner H, Kovacs G, Robert Nicoud M, Lichter P, Cremer T (1993) Detection of complete and partial chromosome gains and losses by comparative genomic in situ hybridization. Hum Genet 90: 590–610
Melmon KL, Rosen SW (1964) Lindau's disease. Review of the literature and study of a large kindred. Am J Med 36: 595–617
Neumann HP (1987) Basic criteria for clinical diagnosis and genetic counselling in von Hippel-Lindau syndrome. Vasa 16: 220–226
Neumann HP, Lips CJM, Hsia YE, Zbar B (1995) Von Hippel-Lindau syndrome. Brain Pathol 5: 181–193
Richards FM, Crossey PA, Phipps ME, Foster K, Latif F, Evans GA, Sampson J, Lerman M, Zbar B, Affara NA, Ferguson-Smith MA, Maher ER (1994) Detailed mapping of germline deletions of the von Hippel-Lindau disease tumour suppressor gene. Hum Mol Genet 3: 595–598
Ried T, Lengauer C, Lipp M, Fischer C, Cremer T, Ward DC (1993) Evaluation of the utility of interphase cytogenetics to detect residual cells with a malignant genotype in mixed cell populations: a Burkitt lymphoma model. DNA Cell Biol 12: 637–643
Ried T, Petersen I, Holtgreve Grez H, Speicher MR, Schrock E, Manoir S du, Cremer T (1994) Mapping of multiple DNA gains and losses in primary small cell lung carcinomas by comparative genomic hybridization. Cancer Res 54: 1801–1806
Seizinger BR, Rouleau GA, Ozelius LJ, Lane AH, Farmer GE, Lamiell JM, Haines J, Yuen JW, Collins D, Majoor Krakauer 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, Decker HJ 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
Sekido Y, Bader S, Latif F, Gnarra JR, Gazdar AF, Linehan WM, Zbar B, Lerman MI, Minna JD (1994) Molecular analysis of the von Hippel-Lindau disease tumor suppressor gene in human lung cancer cell lines. Oncogene 9: 1599–1604
Shuin T, Kondo K, Torigoe S, Kishida T, Kubota Y, Hosaka M, Nagashima Y, Kitamura H, Latif F, Zbar B, Lerman MI, Yao M (1994) Frequent somatic mutations and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas. Cancer Res 54: 2852–2855
Steinbach F, Stöckle M, Müller SC, Thüroff JW, Melchior SW, Stein R, Hohenfellner R (1992) Conservative surgery of renal cell tumors in 140 patients: 21 years of experience. J Urol 148: 24–29
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
Vance JM, Small KW, Jones MA, Stajich JM, Yamaoka LH, Roses AD, Hung WY, Pericak Vance MA (1990) Confirmation of linkage in von Hippel-Lindau disease. Genomics 6: 565–567
Whaley JM, Naglich J, Gelbert L, Hsia YE, Lamiell JM, Green JS, Collins D, Neumann HP, Laidlaw J, Li FP et al (1994) Germline mutations in the von Hippel-Lindau tumor-suppressor gene are similar to somatic von Hippel-Lindau aberrations in sporadic renal cell carcinoma. Am J Hum Genet 55: 1092–1102
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Decker, HJ.H., Neuhaus, C., Jauch, A. et al. Detection of a germline mutation and somatic homozygous loss of the von Hippel-Lindau tumor-suppressor gene in a family with a de novo mutation. Hum Genet 97, 770–776 (1996). https://doi.org/10.1007/BF02346188
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF02346188