Skip to main content
PMC home page
American Journal of Human Genetics logoLink to American Journal of Human Genetics
. 1998 Oct;63(4):1025–1035. doi: 10.1086/302037

An analysis of phenotypic variation in the familial cancer syndrome von Hippel-Lindau disease: evidence for modifier effects.

A R Webster 1, F M Richards 1, F E MacRonald 1, A T Moore 1, E R Maher 1
PMCID: PMC1377470  PMID: 9758595

Abstract

von Hippel-Lindau disease (VHL) is a dominantly inherited familial cancer syndrome predisposing to ocular and CNS hemangioblastomas, renal-cell carcinoma (RCC), and pheochromocytoma. Both interfamilial and intrafamilial variability in expression is well recognized. Interfamilial differences in pheochromocytoma susceptibility have been attributed to allelic heterogeneity such that specific missense germ-line mutations confer a high risk for this complication. However, in most cases, tumor susceptibility does not appear to be influenced by the type of underlying VHL mutation. To probe the causes of phenotypic variation, we examined 183 individuals with germ-line VHL gene mutations, for the presence and number of ocular tumors. The prevalence of ocular angiomatosis did not increase with age, and the distribution of these tumors in gene carriers was significantly different than the expected stochastic distributions. Individuals with ocular hemangioblastomas had a significantly increased incidence of cerebellar hemangioblastoma and RCC (hazard ratios 2.3 and 4.0, respectively). The number of ocular tumors was significantly correlated in individuals of 12 degree relatedness but not in more distantly related individuals. These findings suggest that the development of VHL ocular tumors is determined at an early age and is influenced by genetic and/or environmental modifier effects that act at multiple sites. Functional polymorphisms in the glutathione-S-transferase M1 gene (GSTM1) or the cytochrome P450 2D6 gene (CYP2D6) did not show a significant association with the severity of ocular or renal involvement.

Full Text

The Full Text of this article is available as a PDF (530.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Agúndez J. A., Ledesma M. C., Benítez J., Ladero J. M., Rodríguez-Lescure A., Díaz-Rubio E., Díaz-Rubio M. CYP2D6 genes and risk of liver cancer. Lancet. 1995 Apr 1;345(8953):830–831. doi: 10.1016/s0140-6736(95)92965-7. [DOI] [PubMed] [Google Scholar]
  2. Agúndez J. A., Olivera M., Ladero J. M., Rodriguez-Lescure A., Ledesma M. C., Diaz-Rubio M., Meyer U. A., Benítez J. Increased risk for hepatocellular carcinoma in NAT2-slow acetylators and CYP2D6-rapid metabolizers. Pharmacogenetics. 1996 Dec;6(6):501–512. doi: 10.1097/00008571-199612000-00003. [DOI] [PubMed] [Google Scholar]
  3. Brauch H., Kishida T., Glavac D., Chen F., Pausch F., Höfler H., Latif F., Lerman M. I., Zbar B., Neumann H. P. Von Hippel-Lindau (VHL) disease with pheochromocytoma in the Black Forest region of Germany: evidence for a founder effect. Hum Genet. 1995 May;95(5):551–556. doi: 10.1007/BF00223868. [DOI] [PubMed] [Google Scholar]
  4. Chen F., Kishida T., Yao M., Hustad T., Glavac D., Dean M., Gnarra J. R., Orcutt M. L., Duh F. M., Glenn G. Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype. Hum Mutat. 1995;5(1):66–75. doi: 10.1002/humu.1380050109. [DOI] [PubMed] [Google Scholar]
  5. Clifford S. C., Prowse A. H., Affara N. A., Buys C. H., Maher E. R. Inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene and allelic losses at chromosome arm 3p in primary renal cell carcinoma: evidence for a VHL-independent pathway in clear cell renal tumourigenesis. Genes Chromosomes Cancer. 1998 Jul;22(3):200–209. doi: 10.1002/(sici)1098-2264(199807)22:3<200::aid-gcc5>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
  6. Crossey P. A., Foster K., Richards F. M., Phipps M. E., Latif F., Tory K., Jones M. H., Bentley E., Kumar R., Lerman M. I. Molecular genetic investigations of the mechanism of tumourigenesis in von Hippel-Lindau disease: analysis of allele loss in VHL tumours. Hum Genet. 1994 Jan;93(1):53–58. doi: 10.1007/BF00218913. [DOI] [PubMed] [Google Scholar]
  7. Crossey P. A., Richards F. M., Foster K., Green J. S., Prowse A., Latif F., Lerman M. I., Zbar B., Affara N. A., Ferguson-Smith M. A. Identification of intragenic mutations in the von Hippel-Lindau disease tumour suppressor gene and correlation with disease phenotype. Hum Mol Genet. 1994 Aug;3(8):1303–1308. doi: 10.1093/hmg/3.8.1303. [DOI] [PubMed] [Google Scholar]
  8. Daly A. K., Thomas D. J., Cooper J., Pearson W. R., Neal D. E., Idle J. R. Homozygous deletion of gene for glutathione S-transferase M1 in bladder cancer. BMJ. 1993 Aug 21;307(6902):481–482. doi: 10.1136/bmj.307.6902.481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dietrich W. F., Lander E. S., Smith J. S., Moser A. R., Gould K. A., Luongo C., Borenstein N., Dove W. Genetic identification of Mom-1, a major modifier locus affecting Min-induced intestinal neoplasia in the mouse. Cell. 1993 Nov 19;75(4):631–639. doi: 10.1016/0092-8674(93)90484-8. [DOI] [PubMed] [Google Scholar]
  10. Easton D. F., Ponder M. A., Huson S. M., Ponder B. A. An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes. Am J Hum Genet. 1993 Aug;53(2):305–313. [PMC free article] [PubMed] [Google Scholar]
  11. Foster K., Prowse A., van den Berg A., Fleming S., Hulsbeek M. M., Crossey P. A., Richards F. M., Cairns P., Affara N. A., Ferguson-Smith M. A. Somatic mutations of the von Hippel-Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma. Hum Mol Genet. 1994 Dec;3(12):2169–2173. doi: 10.1093/hmg/3.12.2169. [DOI] [PubMed] [Google Scholar]
  12. Gnarra J. R., Tory K., Weng Y., Schmidt L., Wei M. H., Li H., Latif F., Liu S., Chen F., Duh F. M. Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet. 1994 May;7(1):85–90. doi: 10.1038/ng0594-85. [DOI] [PubMed] [Google Scholar]
  13. Gould K. A., Dietrich W. F., Borenstein N., Lander E. S., Dove W. F. Mom1 is a semi-dominant modifier of intestinal adenoma size and multiplicity in Min/+ mice. Genetics. 1996 Dec;144(4):1769–1776. doi: 10.1093/genetics/144.4.1769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Herman J. G., Latif F., Weng Y., Lerman M. I., Zbar B., Liu S., Samid D., Duan D. S., Gnarra J. R., Linehan W. M. Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9700–9704. doi: 10.1073/pnas.91.21.9700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hirvonen A., Husgafvel-Pursiainen K., Anttila S., Karjalainen A., Vainio H. Polymorphism in CYP1A1 and CYP2D6 genes: possible association with susceptibility to lung cancer. Environ Health Perspect. 1993 Oct;101 (Suppl 3):109–112. doi: 10.1289/ehp.93101s3109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jones M. H., Yamakawa K., Nakamura Y. Isolation and characterization of 19 dinucleotide repeat polymorphisms on chromosome 3p. Hum Mol Genet. 1992 May;1(2):131–133. doi: 10.1093/hmg/1.2.131. [DOI] [PubMed] [Google Scholar]
  17. Kanno H., Kondo K., Ito S., Yamamoto I., Fujii S., Torigoe S., Sakai N., Hosaka M., Shuin T., Yao M. Somatic mutations of the von Hippel-Lindau tumor suppressor gene in sporadic central nervous system hemangioblastomas. Cancer Res. 1994 Sep 15;54(18):4845–4847. [PubMed] [Google Scholar]
  18. Knudson A. G., Jr Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820–823. doi: 10.1073/pnas.68.4.820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Latif F., Tory K., Gnarra J., Yao M., Duh F. M., Orcutt M. L., Stackhouse T., Kuzmin I., Modi W., Geil L. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science. 1993 May 28;260(5112):1317–1320. doi: 10.1126/science.8493574. [DOI] [PubMed] [Google Scholar]
  20. Maher E. R., Kaelin W. G., Jr von Hippel-Lindau disease. Medicine (Baltimore) 1997 Nov;76(6):381–391. doi: 10.1097/00005792-199711000-00001. [DOI] [PubMed] [Google Scholar]
  21. Maher E. R., Webster A. R., Richards F. M., Green J. S., Crossey P. A., Payne S. J., Moore A. T. Phenotypic expression in von Hippel-Lindau disease: correlations with germline VHL gene mutations. J Med Genet. 1996 Apr;33(4):328–332. doi: 10.1136/jmg.33.4.328. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Maher E. R., Yates J. R., Harries R., Benjamin C., Harris R., Moore A. T., Ferguson-Smith M. A. Clinical features and natural history of von Hippel-Lindau disease. Q J Med. 1990 Nov;77(283):1151–1163. doi: 10.1093/qjmed/77.2.1151. [DOI] [PubMed] [Google Scholar]
  23. Oberstrass J., Reifenberger G., Reifenberger J., Wechsler W., Collins V. P. Mutation of the Von Hippel-Lindau tumour suppressor gene in capillary haemangioblastomas of the central nervous system. J Pathol. 1996 Jun;179(2):151–156. doi: 10.1002/(sici)1096-9896(199606)179:2<151::aid-path556>3.0.co;2-0. [DOI] [PubMed] [Google Scholar]
  24. Phelan C. M., Rebbeck T. R., Weber B. L., Devilee P., Ruttledge M. H., Lynch H. T., Lenoir G. M., Stratton M. R., Easton D. F., Ponder B. A. Ovarian cancer risk in BRCA1 carriers is modified by the HRAS1 variable number of tandem repeat (VNTR) locus. Nat Genet. 1996 Mar;12(3):309–311. doi: 10.1038/ng0396-309. [DOI] [PubMed] [Google Scholar]
  25. Prowse A. H., Webster A. R., Richards F. M., Richard S., Olschwang S., Resche F., Affara N. A., Maher E. R. Somatic inactivation of the VHL gene in Von Hippel-Lindau disease tumors. Am J Hum Genet. 1997 Apr;60(4):765–771. [PMC free article] [PubMed] [Google Scholar]
  26. Raunio H., Husgafvel-Pursiainen K., Anttila S., Hietanen E., Hirvonen A., Pelkonen O. Diagnosis of polymorphisms in carcinogen-activating and inactivating enzymes and cancer susceptibility--a review. Gene. 1995 Jun 14;159(1):113–121. doi: 10.1016/0378-1119(94)00448-2. [DOI] [PubMed] [Google Scholar]
  27. Richards F. M., Crossey P. A., Phipps M. E., Foster K., Latif F., Evans G., Sampson J., Lerman M. I., Zbar B., Affara N. A. Detailed mapping of germline deletions of the von Hippel-Lindau disease tumour suppressor gene. Hum Mol Genet. 1994 Apr;3(4):595–598. doi: 10.1093/hmg/3.4.595. [DOI] [PubMed] [Google Scholar]
  28. Richards F. M., Payne S. J., Zbar B., Affara N. A., Ferguson-Smith M. A., Maher E. R. Molecular analysis of de novo germline mutations in the von Hippel-Lindau disease gene. Hum Mol Genet. 1995 Nov;4(11):2139–2143. doi: 10.1093/hmg/4.11.2139. [DOI] [PubMed] [Google Scholar]
  29. Richards F. M., Schofield P. N., Fleming S., Maher E. R. Expression of the von Hippel-Lindau disease tumour suppressor gene during human embryogenesis. Hum Mol Genet. 1996 May;5(5):639–644. doi: 10.1093/hmg/5.5.639. [DOI] [PubMed] [Google Scholar]
  30. Sachse C., Brockmöller J., Bauer S., Roots I. Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences. Am J Hum Genet. 1997 Feb;60(2):284–295. [PMC free article] [PubMed] [Google Scholar]
  31. Smith C. A., Moss J. E., Gough A. C., Spurr N. K., Wolf C. R. Molecular genetic analysis of the cytochrome P450-debrisoquine hydroxylase locus and association with cancer susceptibility. Environ Health Perspect. 1992 Nov;98:107–112. doi: 10.1289/ehp.9298107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Whaley J. M., Naglich J., Gelbert L., Hsia Y. E., Lamiell J. M., Green J. S., Collins D., Neumann H. P., Laidlaw J., Li F. P. Germ-line 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. 1994 Dec;55(6):1092–1102. [PMC free article] [PubMed] [Google Scholar]
  33. Wolf C. R., Smith C. A., Forman D. Metabolic polymorphisms in carcinogen metabolising enzymes and cancer susceptibility. Br Med Bull. 1994 Jul;50(3):718–731. doi: 10.1093/oxfordjournals.bmb.a072920. [DOI] [PubMed] [Google Scholar]
  34. Zbar B., Kishida T., Chen F., Schmidt L., Maher E. R., Richards F. M., Crossey P. A., Webster A. R., Affara N. A., Ferguson-Smith M. A. Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan. Hum Mutat. 1996;8(4):348–357. doi: 10.1002/(SICI)1098-1004(1996)8:4<348::AID-HUMU8>3.0.CO;2-3. [DOI] [PubMed] [Google Scholar]
  35. Zhong S., Howie A. F., Ketterer B., Taylor J., Hayes J. D., Beckett G. J., Wathen C. G., Wolf C. R., Spurr N. K. Glutathione S-transferase mu locus: use of genotyping and phenotyping assays to assess association with lung cancer susceptibility. Carcinogenesis. 1991 Sep;12(9):1533–1537. doi: 10.1093/carcin/12.9.1533. [DOI] [PubMed] [Google Scholar]
  36. Zhong S., Wyllie A. H., Barnes D., Wolf C. R., Spurr N. K. Relationship between the GSTM1 genetic polymorphism and susceptibility to bladder, breast and colon cancer. Carcinogenesis. 1993 Sep;14(9):1821–1824. doi: 10.1093/carcin/14.9.1821. [DOI] [PubMed] [Google Scholar]

Articles from American Journal of Human Genetics are provided here courtesy of American Society of Human Genetics

RESOURCES