Human Genetics

, Volume 83, Issue 2, pp 155–158 | Cite as

Epigenetic changes may contribute to the formation and spontaneous regression of retinoblastoma

  • Valerie Greger
  • Eberhard Passarge
  • Wolfgang Höpping
  • Elmar Messmer
  • Bernhard Horsthemke
Original Investigations

Summary

Epigenetic models for tumor formation assume that oncogenic transformation results from changes in the activity of otherwise normal genes. Since gene activity can be inhibited by DNA methylation, and inactivation of tumor suppressor genes is a fundamental process in oncogenesis, we investigated the methylation status of the retinoblastoma suppressor gene (RB gene) on chromosome 13, in blood and tumor cells from 21 retinoblastoma patients. Using methylation-sensitive restriction enzymes and a cloned DNA probe for the unmethylated CpG island at the 5′ end of RB gene, we obtained evidence of hypermethylation of this gene in a sporadic unilateral retinoblastoma tumor. The closely linked esterase D gene and a CpG-rich island on chromosome 15 were not affected. We suggest that changes in the methylation pattern of the RB gene play a role in the development and spontaneous regression of some retinoblastoma tumors.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Benedict WF, Murphree AL, Banerjee A, Spina CA, Sparkes MC, Sparkes R (1983) Patient with 13 chromosome deletion: evidence that the retinoblastoma gene is a recessive cancer gene. Science 219: 973–975Google Scholar
  2. Bird AP (1986) CpG-rich islands and the function of DNA methylation. Nature 321: 209–213Google Scholar
  3. Bird AP, Southern EM (1978) Use of restriction enzymes to study eukaryotic DNA methylation. I. The methylation pattern in ribosomal DNA from Xenopus laevis. J Mol Biol 118: 27–47Google Scholar
  4. Bookstein R, Lee EYHP, To H, Young LJ, Sery TW, Hayes RC, Friedmann T, Lee WH (1988) Human retinoblastoma susceptibility gene: genomic organisation and analysis of heterozygous intragenic deletion mutants. Proc Natl Acad Sci USA 85: 2210–2214Google Scholar
  5. Buiting K, Passarge E, Horsthemke B (1988) Construction of a chromosome 15-specific linking library and identification of potential gene sequences. Genomics 3: 143–149Google Scholar
  6. Cavenee WK, Dryja TP, Phillips RA, Benedict WF, Godbout R, Gallie BL, Murphree AL, Strong LC, White RL (1983) Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305: 779–784Google Scholar
  7. Chandler LA, Ghazi H, Jones PA, Boukamp P, Fusenig NE (1987) Allele-specific methylation of the human c-Ha-ras-1 gene. Cell 50: 711–717Google Scholar
  8. De Bustros A, Nelkin BD, Silvermann A, Ehrlich G, Poiesz B, Baylin SB (1988) The short arm of chromosome 11 is a “hot spot” for hypermethylation in human neoplasia. Proc Natl Acad Sci USA 85: 5693–5697Google Scholar
  9. Feinberg AP, Vogelstein B (1983) Hypomethylation distinguishes genes of some human cancers from their normal counterparts. Nature 301: 89–92Google Scholar
  10. Friend SH, Bernards R, Rogelj S, Weinberg RA, Rapaport JM, Albert DM, Dryja TA (1986) A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323: 643–646Google Scholar
  11. Fung YKT, Murphree AL, T'Ang A, Quian J, Hinrichs SH, Benedict WF (1987) Structural evidence for the authenticity of the human retinoblastoma gene. Science 236: 1657–1661Google Scholar
  12. Gartler SM, Dyer KA, Graves JAM, Rocchi M (1985) A two step model for mammalian X-chromosome inactivation. In: Cantoni GL, Razin A (eds) Biochemistry and biology of DNA methylation. Liss, New York, pp 223–238Google Scholar
  13. Goelz SE, Vogelstein B, Hamilton B, Feinberg AP (1985) Hypomethylation of DNA from benign and malignant human colon neoplasms. Science 228: 187–190Google Scholar
  14. Holliday R (1987) The inheritance of epigenetic defects. Science 238: 163–170Google Scholar
  15. Horsthemke B, Greger V, Barnert HJ, Höpping W, Passarge E (1987) Detection of submicroscopic deletions and a DNA polymorphism at the retinoblastoma locus. Hum Genet 76: 257–261Google Scholar
  16. Human Gene Mapping 9 (1987) 9th International Workshop on Human Gene Mapping. Cytogenet Cell Genet 46: 1–762Google Scholar
  17. Jahner D, Jaenisch R (1984) DNA methylation in early mammalian development. In: Razin A, Cedar H, Riggs AD (eds) DNA methylation, biochemistry and biological significance. Springer, Berlin Heidelberg New York, pp 189–219Google Scholar
  18. Jones PA (1985) Altering gene expression with 5-azacytidine. Cell 40: 485–486Google Scholar
  19. Kautainien TL, Jones PA (1986) DNA methyltransferase levels in tumorigenic and nontumorigenic cells in culture. J Biol Chem 261: 1594–1598Google Scholar
  20. Klein G (1987) The approaching era of the tumor suppressor genes. Science 238: 1539–1545Google Scholar
  21. Knudson AG (1971) Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci USA 68: 820–823Google Scholar
  22. Kunkel LM, Smith KD, Boyer SH, Borgaonkor DS, Wachtel SS, Miller OJ, Breg WR, Jones HW, Rary JM (1977) Analysis of human Y-chromosome-specific reiterated DNA in chromosome variants. Proc Natl Acad Sci USA 74: 1245–1249Google Scholar
  23. Lee WH, Brookstein R, Hong F, Young LJ, Shew JY, Lee EYHP (1987) Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science 235: 1394–1399Google Scholar
  24. Lyon MF (1988) X-chromosome inactivation and the location and expression of X-linked genes. Am J Hum Genet 42: 8–16Google Scholar
  25. Reik W, Surani MA (1989) Genomic imprinting and embryonal tumours. Nature 338: 112–113Google Scholar
  26. Shmookler-Reis RJ, Goldstein S (1982) Interclonal varation in methylation patterns for expressed and non-expressed genes. Nucleic Acids Res 10: 4293–4304Google Scholar
  27. Silva AJ, White R (1988) Inheritance of allelic blueprints for methylation patterns. Cell 54: 145–152Google Scholar
  28. Sparkes RS, Sparkes MC, Wilson MG, Towner JW, Benedict WF, Murphree AL, Yunis JJ (1980) Regional assignment of esterase D and retinoblastoma to chromosome band 13q14. Science 208: 1042–1044Google Scholar
  29. Squire J, Dryja TP, Dunn J, Goddard A, Hofmann T, Musarella M, Willard HF, Becker AJ, Gallie BL, Phillips RA (1986) Cloning of the esterase D gene: a polymorphic gene probe closely linked to the retinoblastoma locus on chromosome 13. Proc Natl Acad Sci USA 83: 6573–6577Google Scholar
  30. Toguchida J, Ishizaki K, Sasaki MS, Nakamura Y, Ikenaga M, Kato M, Sugimot M, Kotoura Y, Yamamuro T (1989) Preferential mutation of paternally derived RB gene as the initial event in sporadic osteosarcoma. Nature 338: 156–158Google Scholar
  31. Young LJS, Lee EYHP, To H, Bookstein R, Shew JY, Donoso LA, Sery T, Giblin M, Shields JA, Lee WH (1988) Human esterase D gene: complete cDNA sequence, genomic structure, and application in the genetic diagnosis of human retinoblastoma. Hum Genet 79: 137–141Google Scholar

Copyright information

© Springer-Verlag 1989

Authors and Affiliations

  • Valerie Greger
    • 1
  • Eberhard Passarge
    • 1
  • Wolfgang Höpping
    • 2
  • Elmar Messmer
    • 2
  • Bernhard Horsthemke
    • 1
  1. 1.Institut für HumangenetikUniversitätsklinikumEssen 1Germany
  2. 2.Zentrum für AugenheilkundeUniversitätsklinikumEssen 1Germany

Personalised recommendations