Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Sep;85(5):705–712. doi: 10.1054/bjoc.2001.1987

Clinical and molecular stratification of disease risk in medulloblastoma

R Gilbertson 1,2, C Wickramasinghe 3, R Hernan 1,2, V Balaji 3, D Hunt 4, D Jones-Wallace 4, J Crolla 5, R Perry 6, J Lunec 2, A Pearson 7, D Ellison 2,3,6
PMCID: PMC2364121  PMID: 11531256

Abstract

The accurate assessment of disease risk among children with medulloblastoma remains a major challenge to the field of paediatric neuro-oncology. In the current study we investigated the capacity of molecular abnormalities to increase the accuracy of disease risk stratification above that afforded by clinical staging alone. 41 primary medulloblastoma tumour samples were analysed for ErbB2 receptor expression using immunohistochemistry, and for aberrations of chromosome 17 and amplification of the MYC oncogene using fluorescence in situ hybridisation. The ErbB2 receptor and deletion of 17p were detected in 80% and 49% of tumours, respectively. 17p loss occurred either in isolation (20%), or in association with gain of 17q (29%), compatible with an isochromosome of 17q. Amplification of MYC was detected in only 2 tumours. Significant prognostic factors included, ‘metastatic disease’ (P = 0.0006), ‘sub-total tumour resection’ (P = 0.007), ‘high ErbB2 receptor expression’ (P = 0.003) and ‘isolated 17p loss’ (P = 0.003). Combined analysis of clinical and molecular factors enabled greater resolution of disease risk than clinical factors alone, identifying a sub-population of patients with particularly favourable disease outcome. These data support the hypothesis that a combination of clinical and molecular factors may afford a more reliable means of assigning disease risk in patients with medulloblastoma, thereby providing a more accurate basis for targeting therapy in children with this disease. © 2001 Cancer Research Campaign http://www.bjcancer.com

Keywords: medulloblastoma, prognosis, ErbB2, MYC, chromosome 17

Full Text

The Full Text of this article is available as a PDF (118.8 KB).

Selected References

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

  1. Badiali M., Pession A., Basso G., Andreini L., Rigobello L., Galassi E., Giangaspero F. N-myc and c-myc oncogenes amplification in medulloblastomas. Evidence of particularly aggressive behavior of a tumor with c-myc amplification. Tumori. 1991 Apr 30;77(2):118–121. doi: 10.1177/030089169107700205. [DOI] [PubMed] [Google Scholar]
  2. Bailey C. C., Gnekow A., Wellek S., Jones M., Round C., Brown J., Phillips A., Neidhardt M. K. Prospective randomised trial of chemotherapy given before radiotherapy in childhood medulloblastoma. International Society of Paediatric Oncology (SIOP) and the (German) Society of Paediatric Oncology (GPO): SIOP II. Med Pediatr Oncol. 1995 Sep;25(3):166–178. doi: 10.1002/mpo.2950250303. [DOI] [PubMed] [Google Scholar]
  3. Batra S. K., McLendon R. E., Koo J. S., Castelino-Prabhu S., Fuchs H. E., Krischer J. P., Friedman H. S., Bigner D. D., Bigner S. H. Prognostic implications of chromosome 17p deletions in human medulloblastomas. J Neurooncol. 1995;24(1):39–45. doi: 10.1007/BF01052657. [DOI] [PubMed] [Google Scholar]
  4. Biegel J. A., Janss A. J., Raffel C., Sutton L., Rorke L. B., Harper J. M., Phillips P. C. Prognostic significance of chromosome 17p deletions in childhood primitive neuroectodermal tumors (medulloblastomas) of the central nervous system. Clin Cancer Res. 1997 Mar;3(3):473–478. [PubMed] [Google Scholar]
  5. Cobleigh M. A., Vogel C. L., Tripathy D., Robert N. J., Scholl S., Fehrenbacher L., Wolter J. M., Paton V., Shak S., Lieberman G. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999 Sep;17(9):2639–2648. doi: 10.1200/JCO.1999.17.9.2639. [DOI] [PubMed] [Google Scholar]
  6. Cogen P. H. Prognostic significance of molecular genetic markers in childhood brain tumors. Pediatr Neurosurg. 1991;17(5):245–250. doi: 10.1159/000120605. [DOI] [PubMed] [Google Scholar]
  7. Emadian S. M., McDonald J. D., Gerken S. C., Fults D. Correlation of chromosome 17p loss with clinical outcome in medulloblastoma. Clin Cancer Res. 1996 Sep;2(9):1559–1564. [PubMed] [Google Scholar]
  8. Gilbertson R. J., Clifford S. C., MacMeekin W., Meekin W., Wright C., Perry R. H., Kelly P., Pearson A. D., Lunec J. Expression of the ErbB-neuregulin signaling network during human cerebellar development: implications for the biology of medulloblastoma. Cancer Res. 1998 Sep 1;58(17):3932–3941. [PubMed] [Google Scholar]
  9. Gilbertson R. J., Jaros E., Perry R. H., Kelly P. J., Lunec J., Pearson A. D. Mitotic percentage index: a new prognostic factor for childhood medulloblastoma. Eur J Cancer. 1997 Apr;33(4):609–615. doi: 10.1016/s0959-8049(96)00516-3. [DOI] [PubMed] [Google Scholar]
  10. Gilbertson R. J., Perry R. H., Kelly P. J., Pearson A. D., Lunec J. Prognostic significance of HER2 and HER4 coexpression in childhood medulloblastoma. Cancer Res. 1997 Aug 1;57(15):3272–3280. [PubMed] [Google Scholar]
  11. Herms J. W., Behnke J., Bergmann M., Christen H. J., Kolb R., Wilkening M., Markakis E., Hanefeld F., Kretzschmar H. A. Potential prognostic value of C-erbB-2 expression in medulloblastomas in very young children. J Pediatr Hematol Oncol. 1997 Nov-Dec;19(6):510–515. doi: 10.1097/00043426-199711000-00004. [DOI] [PubMed] [Google Scholar]
  12. Herms J., Neidt I., Lüscher B., Sommer A., Schürmann P., Schröder T., Bergmann M., Wilken B., Probst-Cousin S., Hernáiz-Driever P. C-MYC expression in medulloblastoma and its prognostic value. Int J Cancer. 2000 Sep 20;89(5):395–402. [PubMed] [Google Scholar]
  13. Kortmann R. D., Kühl J., Timmermann B., Mittler U., Urban C., Budach V., Richter E., Willich N., Flentje M., Berthold F. Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the German prospective randomized trial HIT '91. Int J Radiat Oncol Biol Phys. 2000 Jan 15;46(2):269–279. doi: 10.1016/s0360-3016(99)00369-7. [DOI] [PubMed] [Google Scholar]
  14. Mantel N. Evaluation of survival data and two new rank order statistics arising in its consideration. Cancer Chemother Rep. 1966 Mar;50(3):163–170. [PubMed] [Google Scholar]
  15. Nicholson J., Wickramasinghe C., Ross F., Crolla J., Ellison D. Imbalances of chromosome 17 in medulloblastomas determined by comparative genomic hybridisation and fluorescence in situ hybridisation. Mol Pathol. 2000 Dec;53(6):313–319. doi: 10.1136/mp.53.6.313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Olayioye M. A., Neve R. M., Lane H. A., Hynes N. E. The ErbB signaling network: receptor heterodimerization in development and cancer. EMBO J. 2000 Jul 3;19(13):3159–3167. doi: 10.1093/emboj/19.13.3159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Packer R. J., Goldwein J., Nicholson H. S., Vezina L. G., Allen J. C., Ris M. D., Muraszko K., Rorke L. B., Wara W. M., Cohen B. H. Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's Cancer Group Study. J Clin Oncol. 1999 Jul;17(7):2127–2136. doi: 10.1200/JCO.1999.17.7.2127. [DOI] [PubMed] [Google Scholar]
  18. Peto R., Pike M. C., Armitage P., Breslow N. E., Cox D. R., Howard S. V., Mantel N., McPherson K., Peto J., Smith P. G. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. II. analysis and examples. Br J Cancer. 1977 Jan;35(1):1–39. doi: 10.1038/bjc.1977.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Scheurlen W. G., Schwabe G. C., Joos S., Mollenhauer J., Sörensen N., Kühl J. Molecular analysis of childhood primitive neuroectodermal tumors defines markers associated with poor outcome. J Clin Oncol. 1998 Jul;16(7):2478–2485. doi: 10.1200/JCO.1998.16.7.2478. [DOI] [PubMed] [Google Scholar]
  20. Scheurlen W. G., Seranski P., Mincheva A., Kühl J., Sörensen N., Krauss J., Lichter P., Poustka A., Wilgenbus K. K. High-resolution deletion mapping of chromosome arm 17p in childhood primitive neuroectodermal tumors reveals a common chromosomal disruption within the Smith-Magenis region, an unstable region in chromosome band 17p11.2. Genes Chromosomes Cancer. 1997 Jan;18(1):50–58. doi: 10.1002/(sici)1098-2264(199701)18:1<50::aid-gcc6>3.0.co;2-0. [DOI] [PubMed] [Google Scholar]
  21. Schwartz C. L. Long-term survivors of childhood cancer: the late effects of therapy. Oncologist. 1999;4(1):45–54. [PubMed] [Google Scholar]
  22. Thomas P. R., Deutsch M., Kepner J. L., Boyett J. M., Krischer J., Aronin P., Albright L., Allen J. C., Packer R. J., Linggood R. Low-stage medulloblastoma: final analysis of trial comparing standard-dose with reduced-dose neuraxis irradiation. J Clin Oncol. 2000 Aug;18(16):3004–3011. doi: 10.1200/JCO.2000.18.16.3004. [DOI] [PubMed] [Google Scholar]
  23. Zeltzer P. M., Boyett J. M., Finlay J. L., Albright A. L., Rorke L. B., Milstein J. M., Allen J. C., Stevens K. R., Stanley P., Li H. Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study. J Clin Oncol. 1999 Mar;17(3):832–845. doi: 10.1200/JCO.1999.17.3.832. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES