Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Preferential amplification of the paternal allele of the N–myc gene in human neuroblastomas

Nature Genetics volume 4, pages 191–194 (1993)Cite this article

Abstract

Genomic imprinting plays a role in influencing the parental origin of genes involved in cancer–specific rearrangements. We have analysed 22 neuroblastomas with N–myc amplification to determine the parental origin of the amplified N–myc allele and the allele that is deleted from chromosome 1p. We analysed DNA from neuroblastoma patients and their parents, using four polymorphisms for 1 p and three for the N–myc amplicon. We determined that the paternal allele of N–myc was preferentially amplified (12 out of 13 cases; P = 0.002). However, the paternal allele was lost from 1 p in six out of ten cases, consistent with a random distribution (P > 0.2). These results suggest that parental imprinting influences which N–myc allele is amplified in neuroblastomas, but it does not appear to affect the 1p allele that is deleted in the cases that we have examined.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Reik, W. Genomic imprinting and genetic disorders in man. Trends Genet. 5, 331–336 (1989).

    Article  CAS  PubMed  Google Scholar 

  2. Sapienza, C. Genome imprinting, cellular mosaicism and carcinogenesis. Molec. Carcinogenet 3, 118–121 (1990).

    Article  CAS  Google Scholar 

  3. Hall, J.G. Genomic imprinting: Review and relevance to human diseases. Am. J. hum. Genet. 46, 857–873 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Sapienza, C., Peterson, A.C., Rossant, J. & Balling, R. Degree of methylation of transgenes is dependent on gamete of origin. Nature 328, 351–354 (1987).

    Article  Google Scholar 

  5. Reik, W., Collick, A., Norris, M.L., Barton, S.C. & Surani, M.A. Genomic imprinting determines methylation of parental alleles in transgenic mice. Nature 328, 248–251 (1987).

    Article  CAS  PubMed  Google Scholar 

  6. Silva, A.J. & White, R. Inheritance of allelic blueprints for methylation patterns. Cell 54, 145–152 (1988).

    Article  CAS  PubMed  Google Scholar 

  7. Nicholls, R.D., Knoll, J.H.M., Butler, M.G., Karam, S. & Lalande, M. Genetic imprinting suggested by maternal heterodisomy in non-deletion Prader-Willi syndrome. Nature 342, 281–285 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Driscoll, D.J. et al. A DNA methylation imprint, determined by the sex of the parent, distinguishes the Angelman and Prader-Willi syndromes. Genomics 13, 917–924 (1992).

    Article  CAS  PubMed  Google Scholar 

  9. Wagstaff, J. et al. Maternal but not paternal transmission of 15q11-13-linked nondeletion Angelman syndrome leads to phenotypic expression. Nature Genet. 1, 291–294 (1992).

    Article  CAS  PubMed  Google Scholar 

  10. Henry, I. et al. Uniparental paternal disomy in a genetic cancer-predisposing syndrome. Nature 351, 665–667 (1991).

    Article  CAS  PubMed  Google Scholar 

  11. Toguchida, J. et al. Preferential mutation of paternally derived RB gene as the initial event in sporadic osteosarcoma. Nature 338, 156–158 (1989).

    Article  CAS  PubMed  Google Scholar 

  12. Dryja, T.P. et al. Parental origin of mutations of the retinoblastoma gene. Nature 339, 556–558 (1989).

    Article  CAS  PubMed  Google Scholar 

  13. Zhu, X. et al. Preferential germline mutation of the paternal allele in retinoblastoma. Nature 340, 312–313 (1989).

    Article  CAS  PubMed  Google Scholar 

  14. Leach, R.J. et al. Preferential retention of paternal alleles in human retinoblastoma: Evidence for genomic imprinting. Cell Growth Diff. 1, 401–406 (1990).

    CAS  PubMed  Google Scholar 

  15. Sakai, T. et al. Allele-specific hypermethylation of the retinoblastoma tumour-suppressor gene. Am. J. Hum. Genet. 48, 880–888 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Schroeder, W.T. et al. Nonrandom loss of maternal chromosome 11 alleles in Wilms tumours. Am. J. hum. Genet. 40, 413–420 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Scrable, H. et al. A model for embryonal rhabdomyosarcoma tumourigenesis that involves genome imprinting. Proc. natn. Acad. Sci. U.S.A. 86, 7480–7484 (1989).

    Article  CAS  Google Scholar 

  18. Williams, J.C., Brown, K.W., Mott, M.G. & Maitland, N.J. Maternal allele loss in Wilms' tumour. Lancet 1, 283–284 (1989).

    Article  CAS  PubMed  Google Scholar 

  19. Royer-Polora, B. & Schneider, S. Wilms' tumour-specific methylation pattern in 11p13 detected by PFGE. Genes Chrom. Cancer 5, 132–140 (1992).

    Article  Google Scholar 

  20. Haas, O.A., Argyriou-Tirita, A. & Lion, T. Parental origin of chromosomes involved in the translocation t(9;22). Nature 359, 414–416 (1992).

    Article  CAS  PubMed  Google Scholar 

  21. Brodeur, G.M., Seeger, R.C., Schwab, M., Varmus, H.E. & Bishop, J.M. Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science 224, 1121–1124 (1984).

    Article  CAS  PubMed  Google Scholar 

  22. Brodeur, G.M. & Fong, C.T. Molecular biology and genetics of human neuroblastoma. Cancer Genet. Cytogenet. 41, 153–174 (1989).

    Article  CAS  PubMed  Google Scholar 

  23. Fong, C.T. et al. Loss of heterozygosity for the short arm of chromosome 1 in human neuroblastomas: Correlation with N-myc amplification. Proc. natn. Acad. Sci. U.S.A. 86, 3753–3757 (1989).

    Article  CAS  Google Scholar 

  24. Brodeur, G.M. Neuroblastoma: Clinical significance of genetic abnormalities. Cancer Surveys 9, 673–688 (1990).

    CAS  PubMed  Google Scholar 

  25. Fong, C.T. et al. Loss of heterozygosity for chromosomes 1 or 14 defines subsets of advanced neuroblastomas. Cancer Res. 52, 1780–1785 (1992).

    CAS  PubMed  Google Scholar 

  26. Kurosawa, H., Yamada, M. & Nakagome, Y. Restriction fragment length polymorphism of the human N-myc gene: relationship to gene amplification. Oncogene 2, 85–90 (1987).

    CAS  PubMed  Google Scholar 

  27. Yamada, M. et al. Amplified allele of the human N-myc oncogene in neuroblastomas. Jpn. J. cancer Res. 79, 670–673 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Waber, P.G., Bowcock, A.M., Arencibia-Mireles, O. & Nisen, P.D. Nonrandom distribution of N-myc oncogene genotypes in neuroblastoma. J. natn. Cancer Inst. 83, 1085–1088 (1991).

    Article  CAS  Google Scholar 

  29. Ramsay, G., Stanton, L., Schwab, M. & Bishop, J.M. Human protooncogene N–myc encodes nuclear proteins that bind DNA. Molec. cell. Biol. 6, 4450–4457 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zehnbauer, B.A., Small, D., Brodeur, G.M., Seeger, R. & Vogelstein, B. Characterization of N-myc amplification units in human neuroblastoma cells. Molec. cell. Biol. 8, 522–530 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Schneider, S.S. et al. Isolation and structural analysis of a 1.2 megabase N-myc amplicon from a human neuroblastoma. Molec. cell. Biol. 12, 5563–5570 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Buroker, N. et al. A hypervariable repeated sequence on human chromosome 1p36. Hum. Genet. 77, 175–181 (1987).

    Article  CAS  PubMed  Google Scholar 

  33. Nakamura, Y. et al. Variable number of tandem repeat (VNTR) markers for human gene mapping. Science 235, 1616–1622 (1984).

    Article  Google Scholar 

  34. Naumova, A. et al. Parental origin of amplified 6p alleles in retinoblastoma. Am. J. hum. Genet. 51, A66 (1992).

    Google Scholar 

  35. Caron, H. et al. Allelic loss of chromosome 1p36 in neuroblastoma is of preferential maternal origin and correlates with N-myc amplification. Nature Genet. 4, 187–190 (1993).

    Article  CAS  PubMed  Google Scholar 

  36. Brodeur, G.M. in Clinical Pediatric Oncology (eds Fernbach, D. J. & Vietti, T.J.) 337–364 (Mosby Year Book, St. Louis, 1991).

    Google Scholar 

  37. Brodeur, G.M. & Castleberry, R.P. in Principles and Practice of Pediatric Oncology (eds Pizzo, P.A. & Poplack, D.G.) 739–767 (J. B. Lippincott Company, Philadelphia, 1993).

    Google Scholar 

  38. Nitschke, R. et al. Localized neuroblastoma treated by surgery—A Pediatric Oncology Group Study. J. clin. Oncol. 6, 1271–1279 (1988).

    Article  CAS  PubMed  Google Scholar 

  39. Forejt, J. & Gregorova, S. Genetic analysis of genomic imprinting: An Imprintor-1 gene controls inactivation of the paternal copy of the mouse Tme locus. Cell 70, 443–450 (1992).

    Article  CAS  PubMed  Google Scholar 

  40. Sapienza, C., Paquette, J., Pannunzio, P., Albrechtson, S. & Morgan, K. The polar-lethal Ovum Mutant gene maps to the distal portion of mouse chromosome 11. Genet. 132, 241–246 (1992).

    CAS  Google Scholar 

  41. Kay, G.F., Penny, G.D., Patel, D. & Ashworth, A. Expression of Xist during mouse development suggests a role in the initiation of X chromosome inactivation. Cell 72, 171–182 (1993).

    Article  CAS  PubMed  Google Scholar 

  42. Sapienza, C., Paquette, J., Tran, T.H. & Peterson, A. Epigenetic and genetic factors affect transgene methylation imprinting. Development 107, 165–168 (1989).

    CAS  PubMed  Google Scholar 

  43. Allen, N.D., Norris, M.L. & Surani, M.A. Epigenetic control of transgene expression and imprinting by genotype-specific modifiers. Cell 61, 853–861 (1990).

    Article  CAS  PubMed  Google Scholar 

  44. Little, M.H. et al. Equivalent expression of paternally and maternally inherited WT1 alleles in normal fetal tissue and Wilms' tumours. Oncogene 7, 635–641 (1992).

    CAS  PubMed  Google Scholar 

  45. Carroll, S. et al. Double minute chromosomes can be produced from precursors derived from a chromosomal deletion. Molec. cell. Biol. 8, 1525–1533 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Stark, G.R., Debatisse, M., Giulotto, E. & Wahl, G.M. Recent progress in understanding mechanisms of mammalian DNA amplification. Cell 57, 901–908 (1989).

    Article  CAS  PubMed  Google Scholar 

  47. Wahl, G.M. The importance of circular DNA in mammalian gene amplification. Cancer Res. 49, 1333–1340 (1989).

    CAS  PubMed  Google Scholar 

  48. Ruiz, J.C. & Wahl, G.M. Chromosomal destabilization during gene amplification. Molec. cell. Biol. 10, 3056–3066 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Zemel, S., Bartolomei, M.S. & Tilghman, S.M. Physical linkage of two mammalian imprinted genes, H19 and insulin-like growth factor 2. Nature Genet. 2, 61–65 (1992).

    Article  CAS  PubMed  Google Scholar 

  50. Kaufman, B.A., White, P.S. & Brodeur, G.M. A complex single strand conformational polymorphism (SSCP) in the tumor necrosis factor receptor 2 (TNFR2) gene on chromosome 1p36.2. Hum. molec. Genet. (in the press).

Download references

Author information

Author notes

  1. Sandra S. Schneider

    Present address: Joint Program in Neonatology, Harvard Medical School, Boston, Massachusetts, 02115, USA

Authors and Affiliations

  1. Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, 63110, USA

    Judy M. Cheng, Jill L. Hiemstra, Sandra S. Schneider & Garrett M. Brodeur

  2. Ludwig Institute for Cancer Research, San Diego, California, 92093, USA

    Anna Naumova & Carmen Sapienza

  3. Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York, 10021, USA

    Nai-Kong V. Cheung

  4. Department of Pediatrics, Children's Memorial Hospital, Chicago, Illinois, 60614, USA

    Susan L. Cohn

  5. Division of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, 02115, USA

    Lisa Diller

  6. The Pediatric Oncology Group, St. Louis, Missouri, 63110, USA

    Garrett M. Brodeur

Authors
  1. Judy M. Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jill L. Hiemstra
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sandra S. Schneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Anna Naumova
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nai-Kong V. Cheung
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Susan L. Cohn
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lisa Diller
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Carmen Sapienza
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Garrett M. Brodeur
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cheng, J., Hiemstra, J., Schneider, S. et al. Preferential amplification of the paternal allele of the N–myc gene in human neuroblastomas. Nat Genet 4, 191–194 (1993). https://doi.org/10.1038/ng0693-191

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng0693-191

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing