Journal of Neuro-Oncology

, Volume 75, Issue 3, pp 273–278 | Cite as

Molecular Biology of Medulloblastoma: Will It Ever Make a Difference to Clinical Management?

Childhood Brain Tumors


Over the last 10 years approximately 750 children with medulloblastoma have been treated on consortia based clinical trials at an estimated cost of over $150 million. Despite this enormous effort, no meaningful molecular data has been generated that will inform the next generation of clinical studies. It is imperative that the neuro-oncology community give greater priority to studies of medulloblastoma molecular biology: unless we do this our patients will face a bleak future in which there is no accurate disease-risk stratification tool and no effective new treatments. We review some of the reasons we have failed to translate knowledge of medulloblastoma disease biology to the clinic and look forward to the next generation of clinical and molecular studies that are seeking to correct this.


DNA gene medulloblastoma microarray molecular targeted therapy 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Gilbertson, RJ 2004Medulloblastoma: signalling a change in treatmentLancet Oncol5209218CrossRefPubMedGoogle Scholar
  2. 2.
    Wasson, JC, Saylors, RL,3rd, Zeltzer, P, Friedman, HS, Bigner, SH, Burger, PC, Bigner, DD, Look, AT, Douglass, EC, Brodeur, GM 1990Oncogene amplification in pediatric brain tumorsCancer Res5029872990PubMedGoogle Scholar
  3. 3.
    Nisen, PD, Zimmerman, KA, Cotter, SV, Gilbert, F, Alt, FW 1986Enhanced expression of the N-myc gene in Wilms’ tumorsCancer Res4662176222PubMedGoogle Scholar
  4. 4.
    Malkin, D, Li, FP, Strong, LC, Fraumeni, JF,Jr., Nelson, CE, Kim, DH, Kassel, J, Gryka, MA, Bischoff, FZ, Tainsky, MA,  et al. 1990Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasmsScience25012331238PubMedGoogle Scholar
  5. 5.
    Saylors, RL,3rd, Sidransky, D,3rd, Friedman, HS, Bigner, SH, Bigner, DD, Vogelstein, B, Brodeur, GM 1991Infrequent p53 gene mutations in medulloblastomasCancer Res5147214723PubMedGoogle Scholar
  6. 6.
    Gajjar, A, Hernan, R, Kocak, M, Fuller, C, Lee, Y, McKinnon, PJ, Wallace, D, Lau, C, Chintagumpala, M, Ashley, DM, Kellie, SJ, Kun, L, Gilbertson, RJ 2004Clinical, histopathologic, and molecular markers of prognosis: toward a new disease risk stratification system for medulloblastomaJ Clin Oncol22984993Epub 2004 Feb 2017CrossRefPubMedGoogle Scholar
  7. 7.
    Gilbertson, RJ, Perry, RH, Kelly, PJ, Pearson, AD, Lunec, J 1997Prognostic significance of HER2 and HER4 coexpression in childhood medulloblastomaCancer Res5732723280PubMedGoogle Scholar
  8. 8.
    Grotzer, MA, Janss, AJ, Fung, K, Biegel, JA, Sutton, LN, Rorke, LB, Zhao, H, Cnaan, A, Phillips, PC, Lee, VM, Trojanowski, JQ 2000TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumorsJ Clin Oncol1810271035PubMedGoogle Scholar
  9. 9.
    Segal, RA, Goumnerova, LC, Kwon, YK, Stiles, CD, Pomeroy, SL 1994Expression of the neurotrophin receptor TrkC is linked to a favorable outcome in medulloblastomaProc Natl Acad Sci U S A911286712871PubMedGoogle Scholar
  10. 10.
    Grotzer, MA, Hogarty, MD, Janss, AJ, Liu, X, Zhao, H, Eggert, A, Sutton, LN, Rorke, LB, Brodeur, GM, Phillips, PC 2001MYC messenger RNA expression predicts survival outcome in childhood primitive neuroectodermal tumor/medulloblastomaClin Cancer Res724252433PubMedGoogle Scholar
  11. 11.
    Herms, J, Neidt, I, Luscher, B, Sommer, A, Schurmann, P, Schroder, T, Bergmann, M, Wilken, B, Probst-Cousin, S, Hernaiz-Driever, P, Behnke, J, Hanefeld, F, Pietsch, T, Kretzschmar, HA 2000C-MYC expression in medulloblastoma and its prognostic valueInt J Cancer89395402CrossRefPubMedGoogle Scholar
  12. 12.
    Jaros, E, Lunec, J, Perry, RH, Kelly, PJ, Pearson, AD 1993p53 protein overexpression identifies a group of central primitive neuroectodermal tumours with poor prognosisBr J Cancer68801807PubMedGoogle Scholar
  13. 13.
    Burns, AS, Jaros, E, Cole, M, Perry, R, Pearson, AJ, Lunec, J 2002The molecular pathology of p53 in primitive neuroectodermal tumours of the central nervous systemBr J Cancer8611171123CrossRefPubMedGoogle Scholar
  14. 14.
    MacDonald, TJ, Brown, KM, LaFleur, B, Peterson, K, Lawlor, C, Chen, Y, Packer, RJ, Cogen, P, Stephan, DA 2001Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic diseaseNat Genet29143152CrossRefPubMedGoogle Scholar
  15. 15.
    Pomeroy, SL, Tamayo, P, Gaasenbeek, M, Sturla, LM, Angelo, M, McLaughlin, ME, Kim, JY, Goumnerova, LC, Black, PM, Lau, C, Allen, JC, Zagzag, D, Olson, JM, Curran, T, Wetmore, C, Biegel, JA, Poggio, T, Mukherjee, S, Rifkin, R, Califano, A, Stolovitzky, G, Louis, DN, Mesirov, JP, Lander, ES, Golub, TR 2002Prediction of central nervous system embryonal tumour outcome based on gene expressionNature415436442CrossRefPubMedGoogle Scholar
  16. 16.
    Vorechovsky, I, Tingby, O, Hartman, M, Stromberg, B, Nister, M, Collins, VP, Toftgard, R 1997Somatic mutations in the human homologue of Drosophila patched in primitive neuroectodermal tumoursOncogene15361366PubMedGoogle Scholar
  17. 17.
    Wolter, M, Reifenberger, J, Sommer, C, Ruzicka, T, Reifenberger, G 1997Mutations in the human homologue of the Drosophila segment polarity gene patched (PTCH) in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous systemCancer Res5725812585PubMedGoogle Scholar
  18. 18.
    Raffel, C, Jenkins, RB, Frederick, L, Hebrink, D, Alderete, B, Fults, DW, James, CD 1997Sporadic medulloblastomas contain PTCH mutationsCancer Res57842845PubMedGoogle Scholar
  19. 19.
    Huang, H, Mahler-Araujo, BM, Sankila, A, Chimelli, L, Yonekawa, Y, Kleihues, P, Ohgaki, H 2000APC mutations in sporadic medulloblastomasAm J Pathol156433437PubMedGoogle Scholar
  20. 20.
    Taylor, MD, Liu, L, Raffel, C, Hui, CC, Mainprize, TG, Zhang, X, Agatep, R, Chiappa, S, Gao, L, Lowrance, A, Hao, A, Goldstein, AM, Stavrou, T, Scherer, SW, Dura, WT, Wainwright, B, Squire, JA, Rutka, JT, Hogg, D 2002Mutations in SUFU predispose to medulloblastomaNat Genet31306310CrossRefPubMedGoogle Scholar
  21. 21.
    Badiali, M, Pession, A, Basso, G, Andreini, L, Rigobello, L, Galassi, E, Giangaspero, F 1991N-myc and c-myc oncogenes amplification in medulloblastomas. Evidence of particularly aggressive behavior of a tumor with c-myc amplificationTumori77118121PubMedGoogle Scholar
  22. 22.
    Gilbertson, RJ, Pearson, AD, Perry, RH, Jaros, E, Kelly, PJ 1995Prognostic significance of the c-erbB-2 oncogene product in childhood medulloblastomaBr J Cancer71473477PubMedGoogle Scholar
  23. 23.
    Fruhwald, MC, O’Dorisio, MS, Dai, Z, Tanner, SM, Balster, DA, Gao, X, Wright, FA, Plass, C 2001Aberrant promoter methylation of previously unidentified target genes is a common abnormality in medulloblastomas – implications for tumor biology and potential clinical utilityOncogene2050335042PubMedGoogle Scholar
  24. 24.
    Lusher, ME, Lindsey, JC, Latif, F, Pearson, AD, Ellison, DW, Clifford, SC 2002Biallelic epigenetic inactivation of the RASSF1A tumor suppressor gene in medulloblastoma developmentCancer Res6259065911PubMedGoogle Scholar
  25. 25.
    Lindsey, JC, Lusher, ME, Anderton, JA, Bailey, S, Gilbertson, RJ, Pearson, AD, Ellison, DW, Clifford, SC 2004Identification of tumour-specific epigenetic events in medulloblastoma development by hypermethylation profilingCarcinogenesis25661668Epub 2003 Dec 2019PubMedGoogle Scholar
  26. 26.
    Ellison, DW, Clifford, SC, Gajjar, A, Gilbertson, RJ 2003What’s new in neuro-oncology? Recent advances in medulloblastomaEur J Paediatr Neurol75366CrossRefPubMedGoogle Scholar
  27. 27.
    Taylor, RE, Bailey, CC, Robinson, K, Weston, CL, Ellison, D, Ironside, J, Lucraft, H, Gilbertson, R, Tait, DM, Walker, DA, Pizer, BL, Imeson, J, Lashford, LS 2003Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: The international society of paediatric oncology/United Kingdom Children’s Cancer Study Group PNET-3 StudyJ Clin Oncol2115811591CrossRefPubMedGoogle Scholar
  28. 28.
    Strother, D, Ashley, D, Kellie, SJ, Patel, A, Jones-Wallace, D, Thompson, S, Heideman, R, Benaim, E, Krance, R, Bowman, L, Gajjar, A 2001Feasibility of four consecutive high-dose chemotherapy cycles with stem-cell rescue for patients with newly diagnosed medulloblastoma or supratentorial primitive neuroectodermal tumor after craniospinal radiotherapy: results of a collaborative studyJ Clin Oncol1926962704PubMedGoogle Scholar
  29. 29.
    Paez, JG, Janne, PA, Lee, JC, Tracy, S, Greulich, H, Gabriel, S, Herman, P, Kaye, FJ, Lindeman, N, Boggon, TJ, Naoki, K, Sasaki, H, Fujii, Y, Eck, MJ, Sellers, WR, Johnson, BE, Meyerson, M 2004EGFR mutations in lung cancer: Correlation with clinical response to Gefitinib therapyScience2929Google Scholar
  30. 30.
    Lynch, TJ, Bell, DW, Sordella, R, Gurubhagavatula, S, Okimoto, RA, Brannigan, BW, Harris, PL, Haserlat, SM, Supko, JG, Haluska, FG, Louis, DN, Christiani, DC, Settleman, J, Haber, DA 2004Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinibN Engl J Med35021292139Epub 2004 Apr 2129CrossRefPubMedGoogle Scholar
  31. 31.
    Hanahan, D, Weinberg, RA 2000The hallmarks of cancerCell1005770CrossRefPubMedGoogle Scholar
  32. 32.
    Venter, JC, Adams, MD, Myers, EW, Li, PW, Mural, RJ, Sutton, GG, Smith, HO, Yandell, M, Evans, CA, Holt, RA, Gocayne, JD, Amanatides, P, Ballew, RM, Huson, DH, Wortman, JR, Zhang, Q, Kodira, CD, Zheng, XH, Chen, L, Skupski, M, Subramanian, G, Thomas, PD, Zhang, J, Gabor Miklos, GL, Nelson, C, Broder, S, Clark, AG, Nadeau, J, McKusick, VA, Zinder, N, Levine, AJ, Roberts, RJ, Simon, M, Slayman, C, Hunkapiller, M, Bolanos, R, Delcher, A, Dew, I, Fasulo, D, Flanigan, M, Florea, L, Halpern, A, Hannenhalli, S, Kravitz, S, Levy, S, Mobarry, C, Reinert, K, Remington, K, Abu-Threideh, J, Beasley, E, Biddick, K, Bonazzi, V, Brandon, R, Cargill, M, Chandramouliswaran, I, Charlab, R, Chaturvedi, K, Deng, Z, Di Francesco, V, Dunn, P, Eilbeck, K, Evangelista, C, Gabrielian, AE, Gan, W, Ge, W, Gong, F, Gu, Z, Guan, P, Heiman, TJ, Higgins, ME, Ji, RR, Ke, Z, Ketchum, KA, Lai, Z, Lei, Y, Li, Z, Li, J, Liang, Y, Lin, X, Lu, F, Merkulov, GV, Milshina, N, Moore, HM, Naik, AK, Narayan, VA, Neelam, B, Nusskern, D, Rusch, DB, Salzberg, S, Shao, W, Shue, B, Sun, J, Wang, Z, Wang, A, Wang, X, Wang, J, Wei, M, Wides, R, Xiao, C, Yan, C, Yao, A, Ye, J, Zhan, M, Zhang, W, Zhang, H, Zhao, Q, Zheng, L, Zhong, F, Zhong, W, Zhu, S, Zhao, S, Gilbert, D, Baumhueter, S, Spier, G, Carter, C, Cravchik, A, Woodage, T, Ali, F, An, H, Awe, A, Baldwin, D, Baden, H, Barnstead, M, Barrow, I, Beeson, K, Busam, D, Carver, A, Center, A, Cheng, ML, Curry, L, Danaher, S, Davenport, L, Desilets, R, Dietz, S, Dodson, K, Doup, L, Ferriera, S, Garg, N, Gluecksmann, A, Hart, B, Haynes, J, Haynes, C, Heiner, C, Hladun, S, Hostin, D, Houck, J, Howland, T, Ibegwam, C, Johnson, J, Kalush, F, Kline, L, Koduru, S, Love, A, Mann, F, May, D, McCawley, S, McIntosh, T, McMullen, I, Moy, M, Moy, L, Murphy, B, Nelson, K, Pfannkoch, C, Pratts, E, Puri, V, Qureshi, H, Reardon, M, Rodriguez, R, Rogers, YH, Romblad, D, Ruhfel, B, Scott, R, Sitter, C, Smallwood, M, Stewart, E, Strong, R, Suh, E, Thomas, R, Tint, NN, Tse, S, Vech, C, Wang, G, Wetter, J, Williams, S, Williams, M, Windsor, S, Winn-Deen, E, Wolfe, K, Zaveri, J, Zaveri, K, Abril, JF, Guigo, R, Campbell, MJ, Sjolander, KV, Karlak, B, Kejariwal, A, Mi, H, Lazareva, B, Hatton, T, Narechania, A, Diemer, K, Muruganujan, A, Guo, N, Sato, S, Bafna, V, Istrail, S, Lippert, R, Schwartz, R, Walenz, B, Yooseph, S, Allen, D, Basu, A, Baxendale, J, Blick, L, Caminha, M, Carnes-Stine, J, Caulk, P, Chiang, YH, Coyne, M, Dahlke, C, Mays, A, Dombroski, M, Donnelly, M, Ely, D, Esparham, S, Fosler, C, Gire, H, Glanowski, S, Glasser, K, Glodek, A, Gorokhov, M, Graham, K, Gropman, B, Harris, M, Heil, J, Henderson, S, Hoover, J, Jennings, D, Jordan, C, Jordan, J, Kasha, J, Kagan, L, Kraft, C, Levitsky, A, Lewis, M, Liu, X, Lopez, J, Ma, D, Majoros, W, McDaniel, J, Murphy, S, Newman, M, Nguyen, T, Nguyen, N, Nodell, M, Pan, S, Peck, J, Peterson, M, Rowe, W, Sanders, R, Scott, J, Simpson, M, Smith, T, Sprague, A, Stockwell, T, Turner, R, Venter, E, Wang, M, Wen, M, Wu, D, Wu, M, Xia, A, Zandieh, A, Zhu, X 2001The sequence of the human genomeScience29113041351CrossRefPubMedGoogle Scholar
  33. 33.
    Ramaswamy, S, Golub, TR 2002DNA microarrays in clinical oncologyJ Clin Oncol2019321941PubMedGoogle Scholar
  34. 34.
    Pinkel, D, Segraves, R, Sudar, D, Clark, S, Poole, I, Kowbel, D, Collins, C, Kuo, WL, Chen, C, Zhai, Y, Dairkee, SH, Ljung, BM, Gray, JW, Albertson, DG 1998High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarraysNat Genet20207211CrossRefPubMedGoogle Scholar
  35. 35.
    Petricoin, EF,3rd, Hackett, JL, Lesko, LJ, Puri, RK, Gutman, SI, Chumakov, K, Woodcock, J, Feigal, DW,Jr., Zoon, KC, Sistare, FD 2002Medical applications of microarray technologies: a regulatory science perspectiveNat Genet32474479CrossRefPubMedGoogle Scholar
  36. 36.
    Liotta, L, Petricoin, E 2000Molecular profiling of human cancerNat Rev Genet14856CrossRefPubMedGoogle Scholar
  37. 37.
    Gilbertson, RJ, Clifford, SC 2003PDGFRB is overexpressed in metastatic medulloblastomaNat Genet35197198CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2005

Authors and Affiliations

  1. 1.Departments of Developmental NeurobiologySt. Jude Children’s Research HospitalMemphisUSA
  2. 2.Hematology/OncologySt. Jude Children’s Research HospitalMemphisUSA

Personalised recommendations