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Correlating telomerase activity levels with human neuroblastoma outcomes

Abstract

Telomerase activity was analysed in 100 neuroblastoma cases. Although telomerase activity was not detected in normal adrenal tissues or benign ganglioneuromas, almost all neuroblastomas (94%) did express it, suggesting an important role for telomerase in neuroblastoma development. Neuroblastomas with high telomerase activity had other genetic changes (for example, N-myc amplification) and an unfavourable prognosis, whereas tumours with low telomerase activity were devoid of such genetic alterations and were associated with a favourable prognosis. Three neuroblastomas lacking telomerase activity regressed (stage IVS). Thus telomerase expression may be required as a critical step in the multigenetic process of tumorigenesis, and two different pathways may exist for the development of neuroblastoma.

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References

  1. Blackburn, E.H., Telomerases. Annu. Rev. Biochem. 61, 113–129 (1992).

    CAS  PubMed  Google Scholar 

  2. Zakian, V.A. Structure and function of telomeres. Annu. Rev Genet. 23, 579–604 (1989).

    CAS  PubMed  Google Scholar 

  3. De Lange, T. Activation of telomerase in a human tumour. Proc. natn. Acad. Sci. U. S.A. 91, 2882–2885 (1994).

    CAS  Google Scholar 

  4. Watson, J.D. Origin of concatemeric T7 DNA. Nature New Biolo. (London) 239, 197–201 (1972).

    CAS  Google Scholar 

  5. Olovnikov, A.M. A theory of marginotomy. J. Theor. Biol. 41, 181–190 (1973).

    CAS  PubMed  Google Scholar 

  6. Levy, M.Z., Allsopp, R.C., Futcher, A.B., Greider, C.W. & Harley, C.B. Telomere end-replication problem and cell aging. J. molec. Biol. 225, 951–960 (1992).

    CAS  PubMed  Google Scholar 

  7. Harley, C.B., Futcher, A.B. & Greider, C.W. Telomeres shorten during ageing of human flbroblasts. Nature 345, 458–460 (1990)

    CAS  PubMed  Google Scholar 

  8. Allsopp, R.C. et al. Telomere length predicts replicative capacity of human fibroblasts. Proc. natn. Acad. Sci. U.S.A. 89, 10114–10118 (1992).

    CAS  Google Scholar 

  9. Vaziri, H. et al. Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. Am. J. Hum. Genet. 52, 661–669 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Shay, J.W., Wright, W.E., Brasiskyte, D. & Van Der Haegen, B.A. E6 of human papillomavirus type 16 can overcome the Ml stage of immortalization in human mammary epithelial cells but not in human flbroblasts. Oncogene 8, 1407–1413 (1993).

    CAS  PubMed  Google Scholar 

  11. Shay, J.W., Wright, W.E. & Werbin, H. Toward a molecular understanding of human breast cancer: a hypothesis. Breast Cancer. Res. Treat, 25, 83–94 (1993).

    CAS  PubMed  Google Scholar 

  12. Kim, N-W. et al. Specific association of human telomerase activity with immortal cells and cancer. Science, 266, 2011–2015 (1994).

    CAS  PubMed  Google Scholar 

  13. Mantell, L.L. & Greider, C.W. Telomerase activity in germline and embryonic cells of Xenopus . EMBO J. 13, 3211–3217 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Counter, C.M. et al. Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity. EMBO J. 11, 1921–1929 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Morin, G.B. The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell 59, 521–529 (1989).

    CAS  PubMed  Google Scholar 

  16. Greider, C.W., Telomeres, telomerase and senescence. Bioessays 12, 363–369 (1990).

    CAS  PubMed  Google Scholar 

  17. Greider, C.W. & Blackburn, E.H. Identification of a specific telomere terminal transferase activity in Tetrahymena extracts. Cell 43, 405–113 (1985).

    CAS  PubMed  Google Scholar 

  18. Allshire, R.C., Dempster, M. & Hastie, N.D. Human telomeres contain at least three types of G-rich repeat distributed non-randomly. Nucl. Acids Res. 17, 4611–4627 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Hastie, N.D. et al. Telomere reduction in human colorectal carcinoma and with ageing. Nature 346, 866–868 (1990).

    CAS  PubMed  Google Scholar 

  20. Lindsey, J., McGill, N.I., Lindsey, L.A., Green, D.K. & Cooke, H.J. In vivo loss of telomeric repeats with age in humans. Mutat. Res. 256, 45–48 (1991).

    CAS  PubMed  Google Scholar 

  21. Harley, C.B. Telomere loss: Mitotic clock or genetic time bomb. Mutat. Res. 256, 271–282 (1991).

    CAS  PubMed  Google Scholar 

  22. Wright, W.E. & Shay, J.W. Telomere positional effects and the regulation of cellular senescence. Trends Genet. 8, 193–198 (1992).

    CAS  PubMed  Google Scholar 

  23. Shay, J.W., Wright, W.E. & Werbin, H. Loss of telomeric DNA during aging may predispose Cells to cancer (Review). Int. J. Oncol. 3, 559–563 (1993).

    CAS  PubMed  Google Scholar 

  24. Wright, W.E. & Shay, J.W. The two-stage mechanism controlling cellular senescence and immortalization. Exp. Geront. 27, 383–389 (1992).

    CAS  Google Scholar 

  25. Shay, J.W., Werbin, H. & Wright, W.E. Telomere shortening may contribute to aging and cancer: A perspective. Molec. Cell. Diff. 2, 1–21 (1994).

    CAS  Google Scholar 

  26. Counter, C.M., Botelho, F.M., Wang, P., Harely, C.B. & Bacchetti, S. Stabilization of short telomeres and telomerase activity accompany immortalization of Epstein-Barr virus transformed human B lymphocytes. J. Virol. 68, 3410–3414 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Counter, C.M., Hirte, H.W., Bacchetti, S. & Harley, C.B. Telomerase activity in human ovarian carcinoma. Proc. natn. Acad. Sci. U.S.A. 91, 2900–2904 (1994).

    CAS  Google Scholar 

  28. Shay, J.W., Tomlinson, G., Piatyszek, M.A. & Gollahon, L. Spontaneous in vitro immortalization of breast epithelial cells from a Li-Fraumeni patient. Molec. Cell. Biol. 15, 425–432 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Young, J.L., Ries, L.G., Silverberg, E., Horm, J.W. & Miller, R.W. Cancer incidence, survival, and mortality for children younger than age 15 years. Cancer 56, 598–602 (1986).

    Google Scholar 

  30. Sawada, T. et al. Long-term effects of mass screening for neuroblastoma in infancy. Am. J. Pediatr. Hematol. Oncol. 13, 3–7 (1991).

    CAS  PubMed  Google Scholar 

  31. Evans, A.E., Gerson, J. & Schnaufer, L. Spontaneous regression of neuroblastoma. Natn. Cancer Inst. Monogr. 44, 49–54 (1976).

    CAS  Google Scholar 

  32. Woods, W.G., Lemieux, B. & Tuchman, M. Neuroblastoma represents distinct clinical–biologic entities: A review and perspective from the Quebec neuroblastoma screening project. Pediatrics 89, 114–118 (1992).

    CAS  PubMed  Google Scholar 

  33. Brodeur, G.M. et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J. Clin. Oncol. 11, 1466–1477 (1993).

    CAS  PubMed  Google Scholar 

  34. 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).

    CAS  PubMed  Google Scholar 

  35. D'Angio, G.J., Evans, A.E. & Koop, C.E. Special pattern of widespread neuroblastoma with a favorable prognosis. Lancet i, 1046–1049 (1971).

    Google Scholar 

  36. Evans, A.E., Baum, E. & Chard, R. Do infants with stage IV-S neuroblastoma need treatment? Arch. Dis. Child 56, 271–274 (1981).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Kretschmar, C.S. et al. Improved prognosis for infants with stage IV neuroblastoma. J. Clin. Oncol. 2, 799–803 (1984).

    CAS  PubMed  Google Scholar 

  38. Finklestein, J.Z. et al. Multiagent chemotherapy for children with metastatic neuroblastoma: a report from Childrens Cancer Study Group. Med. Pediatr. Oncol. 6, 179–188 (1979).

    CAS  PubMed  Google Scholar 

  39. Evans, A.E., D'Angio, G.J. & Randolf, J. A proposed staging for children with neuroblastoma. Cancer 27, 374–378 (1971).

    CAS  PubMed  Google Scholar 

  40. Seeger, R.C. et al. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. New Engl. J. Med. 313, 1111–1116 (1985).

    CAS  PubMed  Google Scholar 

  41. Hayashi, Y. et al. Cytogenetic findings and prognosis in neuroblastoma with emphasis on marker chromosome 1. Cancer 63, 126–132 (1989).

    CAS  PubMed  Google Scholar 

  42. Fong, C. 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).

    CAS  Google Scholar 

  43. Hellstrom, I., Hellstrom, K.E., Pierce, G.E. & Bill, A.H. Demonstration of cell-bound and humoral immunity against neuroblastoma cells. Proc. natn. Acad. Sci. U.S.A. 60, 1231–1238 (1968).

    CAS  Google Scholar 

  44. Rangecroft, L., Lauder, I. & Wagget, J. Spontaneous maturation of stage IV-S neuroblastoma. Arch Dis. Child 52, 815–817 (1978).

    Google Scholar 

  45. Hiyama, E., Hiyama, K., Yokoyama, T., Ichikawa, T. & Matsuura, Y. Length of telomeric repeats in neuroblastoma: Correlation with prognosis and other biological characteristics. Jap. J. Cancer Res. 83, 159–164 (1992).

    CAS  Google Scholar 

  46. Shimada, H. et al. Histopathologic prognostic factors in neuroblastic tumours. J. natn. Cancer Inst. 73, 405–416 (1984).

    CAS  Google Scholar 

  47. Hiyama, E. et al. Alteration of telomeric repeat length in adult and childhood solid neoplasias. Int. J. Oncol. 6, 13–16 (1995).

    CAS  PubMed  Google Scholar 

  48. Turkel, S.B. & Itabashi, H.H. The natural history of neuroblastic cells in the fetal adrenal gland. Am. J. Path. 76, 225–244 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Ikeda, Y., Lister, J., Bouton, J.M. & Buyukpamukcu, M. Congenital neuroblastoma, neuroblastoma in situ, and the normal fetal development of the adrenal. J. Pediatr. Surg. 16, 636–644 (1981).

    CAS  PubMed  Google Scholar 

  50. Schwartz, H.S., Dhair, G.A. & Butler, M.G. Telomere reduction in giant cell tumour of bone and with age. Cancer Genet. Cytogenet. 71, 132–138 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Mehle, C., Ljungberg, B. & Roos, G. Telomere shortening in renal cell carcinoma. Cancer Res. 54, 236–241 (1994).

    CAS  PubMed  Google Scholar 

  52. Nürnberg, P., Thiel, G., Weber, F. & Epplen, J.T. Changes of telomere lengths in human intracranial tumours. Human Genet. 91, 190–192 (1993).

    Google Scholar 

  53. Schmitt, H., Blin, N., Zankl, H. & Scherthan, H. Telomere length variation in normal and malignant human tissue. Genes Chrom. & Cancer 11, 171–177 (1994).

    CAS  Google Scholar 

  54. Prichard, J. & Hickman, J.A. Why does stage 4s neuroblastoma regress spontaneously? Lancet 344, 869–870 (1994).

    Google Scholar 

  55. James, D.H., Hutsu, O., Wrenn, E.L. & Pinkel, D. Combination chemotherapy of childhood neuroblastoma. JAMA 194, 123–126 (1965).

    Google Scholar 

  56. Sawaguchi, S. et al. Treatment of advanced neuroblastoma with emphasis on intensive induction chemotherapy: a report from the Study Group of Japan. Cancer 66, 1879–1887 (1990).

    CAS  PubMed  Google Scholar 

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Hiyama, E., Hiyama, K., Yokoyama, T. et al. Correlating telomerase activity levels with human neuroblastoma outcomes. Nat Med 1, 249–255 (1995). https://doi.org/10.1038/nm0395-249

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