Skip to main content
SpringerLink
Log in

Medulloblastoma and CNS Primitive Neuroectodermal Tumors

  • Chapter
  • First Online:
Molecular Pathology of Nervous System Tumors

Part of the book series: Molecular Pathology Library ((MPLB,volume 8))

  • 2078 Accesses

Abstract

Medulloblastoma and CNS-PNET are malignant embryonal tumors arising predominantly in children (although they can also occur in adults), which share a number of clinical and histological similarities. They are primarily discriminated based on location (medulloblastomas are infratentorial, while the term CNS-PNET is used for tumors outside of the cerebellum). Medulloblastomas typically show differentiation along a neuronal lineage, while CNS-PNETs display a more diverse pattern. Several histological variants are described for each entity, and it is now becoming clear that these tumors are also comprised of distinct biological subgroups with a high degree of molecular heterogeneity. A wealth of detailed genomic information has been generated for medulloblastoma in recent years, including large copy number, transcriptome and next-generation sequencing datasets, which has greatly improved our understanding of the alterations driving this disease. The progress on CNS-PNET has been somewhat more modest, partly due to the scarcity of good material for biological studies. The pace of research on this under-studied entity (or group of entities) is starting to build, however, and has led to the recognition of different molecular subgroups. In this chapter, we summarize these recent advances and the current knowledge relating to the molecular pathology of medulloblastoma and CNS-PNET, and provide an outlook as to how these exciting new findings may be built upon in order to translate them to the clinic.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 179.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO classification of tumors of the central nervous system. LYON: IARC Press; 2007.

    Google Scholar 

  2. Jakacki RI, Burger PC, Zhou T, Holmes EJ, Kocak M, Onar A, et al. Outcome of children with metastatic medulloblastoma treated with carboplatin during craniospinal radiotherapy: a Children’s Oncology Group Phase I/II study. J Clin Oncol. 2012;30(21):2648–53.

    CAS  PubMed  Google Scholar 

  3. Ellison DW, Kocak M, Dalton J, Megahed H, Lusher ME, Ryan SL, et al. Definition of disease-risk stratification groups in childhood medulloblastoma using combined clinical, pathologic, and molecular variables. J Clin Oncol. 2011;29(11):1400–7.

    PubMed Central  PubMed  Google Scholar 

  4. Gajjar A, Chintagumpala M, Ashley D, Kellie S, Kun LE, Merchant TE, et al. Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol. 2006;7(10):813–20.

    PubMed  Google Scholar 

  5. Giangaspero F, Wellek S, Masuoka J, Gessi M, Kleihues P, Ohgaki H. Stratification of medulloblastoma on the basis of histopathological grading. Acta Neuropathol. 2006;112(1):5–12.

    PubMed  Google Scholar 

  6. Rutkowski S, von Hoff K, Emser A, Zwiener I, Pietsch T, Figarella-Branger D, et al. Survival and prognostic factors of early childhood medulloblastoma: an international meta-analysis. J Clin Oncol. 2010;28(33):4961–8.

    PubMed  Google Scholar 

  7. Brown HG, Kepner JL, Perlman EJ, Friedman HS, Strother DR, Duffner PK, et al. “Large cell/anaplastic” medulloblastomas: a Pediatric Oncology Group Study. J Neuropathol Exp Neurol. 2000;59(10):857–65.

    CAS  PubMed  Google Scholar 

  8. Northcott PA, Rutka JT, Taylor MD. Genomics of medulloblastoma: from Giemsa-banding to next-generation sequencing in 20 years. Neurosurg Focus. 2010;28(1):E6.

    PubMed  Google Scholar 

  9. Scheurlen WG, Schwabe GC, Joos S, Mollenhauer J, Sorensen N, Kuhl J. Molecular analysis of childhood primitive neuroectodermal tumors defines markers associated with poor outcome. J Clin Oncol. 1998;16(7):2478–85.

    CAS  PubMed  Google Scholar 

  10. Badiali M, Pession A, Basso G, Andreini L, Rigobello L, Galassi E, et al. N-myc and c-myc oncogenes amplification in medulloblastomas. Evidence of particularly aggressive behavior of a tumor with c-myc amplification. Tumori. 1991;77(2):118–21.

    CAS  PubMed  Google Scholar 

  11. Giangaspero F, Rigobello L, Badiali M, Loda M, Andreini L, Basso G, et al. Large-cell medulloblastomas. A distinct variant with highly aggressive behavior. Am J Surg Pathol. 1992;16(7):687–93.

    CAS  PubMed  Google Scholar 

  12. Aldosari N, Bigner SH, Burger PC, Becker L, Kepner JL, Friedman HS, et al. MYCC and MYCN oncogene amplification in medulloblastoma. A fluorescence in situ hybridization study on paraffin sections from the Children’s Oncology Group. Arch Pathol Lab Med. 2002;126(5):540–4.

    PubMed  Google Scholar 

  13. Lamont JM, McManamy CS, Pearson AD, Clifford SC, Ellison DW. Combined histopathological and molecular cytogenetic stratification of medulloblastoma patients. Clin Cancer Res. 2004;10(16):5482–93.

    CAS  PubMed  Google Scholar 

  14. Pfister S, Remke M, Benner A, Mendrzyk F, Toedt G, Felsberg J, et al. Outcome prediction in pediatric medulloblastoma based on DNA copy-number aberrations of chromosomes 6q and 17q and the MYC and MYCN loci. J Clin Oncol. 2009;27(10):1627–36.

    PubMed  Google Scholar 

  15. von Hoff K, Hartmann W, von Bueren AO, Gerber NU, Grotzer MA, Pietsch T, et al. Large cell/anaplastic medulloblastoma: outcome according to myc status, histopathological, and clinical risk factors. Pediatr Blood Cancer. 2010;54(3):369–76.

    Google Scholar 

  16. Ryan SL, Schwalbe EC, Cole M, Lu Y, Lusher ME, Megahed H, et al. MYC family amplification and clinical risk-factors interact to predict an extremely poor prognosis in childhood medulloblastoma. Acta Neuropathol. 2012;123(4):501–13.

    CAS  PubMed  Google Scholar 

  17. Taylor MD, Mainprize TG, Rutka JT. Molecular insight into medulloblastoma and central nervous system primitive neuroectodermal tumor biology from hereditary syndromes: a review. Neurosurgery. 2000;47(4):888–901.

    CAS  PubMed  Google Scholar 

  18. Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996;85(6):841–51.

    CAS  PubMed  Google Scholar 

  19. Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 1996;272(5268):1668–71.

    CAS  PubMed  Google Scholar 

  20. Gailani MR, Bale SJ, Leffell DJ, DiGiovanna JJ, Peck GL, Poliak S, et al. Developmental defects in Gorlin syndrome related to a putative tumor suppressor gene on chromosome 9. Cell. 1992;69(1):111–7.

    CAS  PubMed  Google Scholar 

  21. Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, et al. The molecular basis of Turcot’s syndrome. N Engl J Med. 1995;332(13):839–47.

    CAS  PubMed  Google Scholar 

  22. Garre ML, Cama A, Bagnasco F, Morana G, Giangaspero F, Brisigotti M, et al. Medulloblastoma variants: age-dependent occurrence and relation to Gorlin syndrome—a new clinical perspective. Clin Cancer Res. 2009;15(7):2463–71.

    PubMed  Google Scholar 

  23. Pomeroy SL, Tamayo P, Gaasenbeek M, Sturla LM, Angelo M, McLaughlin ME, et al. Prediction of central nervous system embryonal tumor outcome based on gene expression. Nature. 2002;415(6870):436–42.

    CAS  PubMed  Google Scholar 

  24. Cho YJ, Tsherniak A, Tamayo P, Santagata S, Ligon A, Greulich H, et al. Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J Clin Oncol. 2011;29(11):1424–30.

    PubMed Central  PubMed  Google Scholar 

  25. Kool M, Koster J, Bunt J, Hasselt NE, Lakeman A, van Sluis P, et al. Integrated genomics identifies five medulloblastoma subtypes with distinct genetic profiles, pathway signatures and clinicopathological features. PLoS One. 2008;3(8):e3088.

    PubMed Central  PubMed  Google Scholar 

  26. Thompson MC, Fuller C, Hogg TL, Dalton J, Finkelstein D, Lau CC, et al. Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations. J Clin Oncol. 2006;24(12):1924–31.

    CAS  PubMed  Google Scholar 

  27. Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S, et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol. 2011;29(11):1408–14.

    PubMed  Google Scholar 

  28. Remke M, Hielscher T, Korshunov A, Northcott PA, Bender S, Kool M, et al. FSTL5 is a marker of poor prognosis in non-WNT/non-SHH medulloblastoma. J Clin Oncol. 2011;29(29):3852–61.

    CAS  PubMed  Google Scholar 

  29. Northcott PA, Korshunov A, Pfister SM, Taylor MD. The clinical implications of medulloblastoma subgroups. Nat Rev Neurol. 2012;8:340–51.

    CAS  PubMed  Google Scholar 

  30. Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012;123(4):465–72.

    CAS  PubMed Central  PubMed  Google Scholar 

  31. Ellison DW, Onilude OE, Lindsey JC, Lusher ME, Weston CL, Taylor RE, et al. beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children’s Cancer Study Group Brain Tumor Committee. J Clin Oncol. 2005;23(31):7951–7.

    CAS  PubMed  Google Scholar 

  32. Kool M, Korshunov A, Remke M, Jones DT, Schlanstein M, Northcott PA, et al. Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol. 2012;123(4):473–84.

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Northcott PA, Jones DT, Kool M, Robinson GW, Gilbertson RJ, Cho YJ, et al. Medulloblastomics: the end of the beginning. Nat Rev Cancer. 2012;12(12):818–34.

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T, et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature. 2012;488(7409):49–56.

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Ellison DW, Dalton J, Kocak M, Nicholson SL, Fraga C, Neale G, et al. Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol. 2011;121(3):381–96.

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Northcott PA, Hielscher T, Dubuc A, Mack S, Shih D, Remke M, et al. Pediatric and adult sonic hedgehog medulloblastomas are clinically and molecularly distinct. Acta Neuropathol. 2011;122(2):231–40.

    PubMed  Google Scholar 

  37. Zhukova N, Ramaswamy V, Remke M, Pfaff E, Shih DJ, Martin DC, et al. Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma. J Clin Oncol. 2013;31(23):2927–35.

    PubMed  Google Scholar 

  38. Brugieres L, Remenieras A, Pierron G, Varlet P, Forget S, Byrde V, et al. High frequency of germline SUFU mutations in children with desmoplastic/nodular medulloblastoma younger than 3 years of age. J Clin Oncol. 2012;30(17):2087–93.

    CAS  PubMed  Google Scholar 

  39. Brugieres L, Pierron G, Chompret A, Paillerets BB, Di Rocco F, Varlet P, et al. Incomplete penetrance of the predisposition to medulloblastoma associated with germ-line SUFU mutations. J Med Genet. 2010;47(2):142–4.

    CAS  PubMed  Google Scholar 

  40. Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X, et al. Mutations in SUFU predispose to medulloblastoma. Nat Genet. 2002;31(3):306–10.

    CAS  PubMed  Google Scholar 

  41. Al-Halabi H, Nantel A, Klekner A, Guiot MC, Albrecht S, Hauser P, et al. Preponderance of sonic hedgehog pathway activation characterizes adult medulloblastoma. Acta Neuropathol. 2011;121(2):229–39.

    PubMed  Google Scholar 

  42. Remke M, Hielscher T, Northcott PA, Witt H, Ryzhova M, Wittmann A, et al. Adult medulloblastoma comprises three major molecular variants. J Clin Oncol. 2011;29(19):2717–23.

    PubMed  Google Scholar 

  43. Korshunov A, Remke M, Kool M, Hielscher T, Northcott PA, Williamson D, et al. Biological and clinical heterogeneity of MYCN-amplified medulloblastoma. Acta Neuropathol. 2012;123(4):515–27.

    CAS  PubMed  Google Scholar 

  44. Meyerson M, Gabriel S, Getz G. Advances in understanding cancer genomes through second-generation sequencing. Nat Rev Genet. 2010;11(10):685–96.

    CAS  PubMed  Google Scholar 

  45. Stratton MR. Exploring the genomes of cancer cells: progress and promise. Science. 2011;331(6024):1553–8.

    CAS  PubMed  Google Scholar 

  46. Pfaff E, Remke M, Sturm D, Benner A, Witt H, Milde T, et al. TP53 mutation is frequently associated with CTNNB1 mutation or MYCN amplification and is compatible with long-term survival in medulloblastoma. J Clin Oncol. 2010;28(35):5188–96.

    CAS  PubMed  Google Scholar 

  47. Srivastava S, Zou ZQ, Pirollo K, Blattner W, Chang EH. Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature. 1990;348(6303):747–9.

    CAS  PubMed  Google Scholar 

  48. Malkin D, Li FP, Strong LC, Fraumeni Jr JF, Nelson CE, Kim DH, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990;250(4985):1233–8.

    CAS  PubMed  Google Scholar 

  49. Rausch T, Jones DT, Zapatka M, Stutz AM, Zichner T, Weischenfeldt J, et al. Genome sequencing of pediatric medulloblastoma links catastrophic DNA rearrangements with TP53 mutations. Cell. 2012;148(1–2):59–71.

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Bunt J, Hasselt NE, Zwijnenburg DA, Koster J, Versteeg R, Kool M. Joint binding of OTX2 and MYC in promotor regions is associated with high gene expression in medulloblastoma. PLoS One. 2011;6(10):e26058.

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Bunt J, Hasselt NE, Zwijnenburg DA, Hamdi M, Koster J, Versteeg R, et al. OTX2 directly activates cell cycle genes and inhibits differentiation in medulloblastoma cells. Int J Cancer. 2012;131:E21–32.

    CAS  PubMed  Google Scholar 

  52. Bunt J, de Haas TG, Hasselt NE, Zwijnenburg DA, Koster J, Versteeg R, et al. Regulation of cell cycle genes and induction of senescence by overexpression of OTX2 in medulloblastoma cell lines. Mol Cancer Res. 2010;8(10):1344–57.

    CAS  PubMed  Google Scholar 

  53. Boon K, Eberhart CG, Riggins GJ. Genomic amplification of orthodenticle homologue 2 in medulloblastomas. Cancer Res. 2005;65(3):703–7.

    CAS  PubMed  Google Scholar 

  54. Di C, Liao S, Adamson DC, Parrett TJ, Broderick DK, Shi Q, et al. Identification of OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans retinoic acid. Cancer Res. 2005;65(3):919–24.

    CAS  PubMed  Google Scholar 

  55. Adamson DC, Shi Q, Wortham M, Northcott PA, Di C, Duncan CG, et al. OTX2 is critical for the maintenance and progression of Shh-independent medulloblastomas. Cancer Res. 2010;70(1):181–91.

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Fernandez LA, Northcott PA, Dalton J, Fraga C, Ellison D, Angers S, et al. YAP1 is amplified and up-regulated in hedgehog-associated medulloblastomas and mediates Sonic hedgehog-driven neural precursor proliferation. Genes Dev. 2009;23(23):2729–41.

    Google Scholar 

  57. Northcott PA, Fernandez LA, Hagan JP, Ellison DW, Grajkowska W, Gillespie Y, et al. The miR-17/92 polycistron is up-regulated in sonic hedgehog-driven medulloblastomas and induced by N-myc in sonic hedgehog-treated cerebellar neural precursors. Cancer Res. 2009;69(8):3249–55.

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Jones DT, Jager N, Kool M, Zichner T, Hutter B, Sultan M, et al. Dissecting the genomic complexity underlying medulloblastoma. Nature. 2012;488:100–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Pugh TJ, Weeraratne SD, Archer TC, Pomeranz Krummel DA, Auclair D, Bochicchio J, et al. Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature. 2012;488:106–10.

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Robinson G, Parker M, Kranenburg TA, Lu C, Chen X, Ding L, et al. Novel mutations target distinct subgroups of medulloblastoma. Nature. 2012;488:43–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Pek JW, Kai T. DEAD-box RNA helicase Belle/DDX3 and the RNA interference pathway promote mitotic chromosome segregation. Proc Natl Acad Sci U S A. 2011;108(29):12007–12.

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Lai MC, Chang WC, Shieh SY, Tarn WY. DDX3 regulates cell growth through translational control of cyclin E1. Mol Cell Biol. 2010;30(22):5444–53.

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Lai MC, Lee YH, Tarn WY. The DEAD-box RNA helicase DDX3 associates with export messenger ribonucleoproteins as well as tip-associated protein and participates in translational control. Mol Biol Cell. 2008;19(9):3847–58.

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Rosner A, Rinkevich B. The DDX3 subfamily of the DEAD box helicases: divergent roles as unveiled by studying different organisms and in vitro assays. Curr Med Chem. 2007;14(23):2517–25.

    CAS  PubMed  Google Scholar 

  65. Jones DT, Northcott PA, Kool M, Pfister SM. The role of chromatin remodeling in medulloblastoma. Brain Pathol. 2013;23(2):193–9.

    CAS  PubMed  Google Scholar 

  66. Batora NV, Sturm D, Jones DT, Kool M, Pfister SM, Northcott PA. Transitioning from genotypes to epigenotypes: why the time has come for medulloblastoma epigenomics. Neuroscience. 2014;264:171–85.

    CAS  PubMed  Google Scholar 

  67. Northcott PA, Nakahara Y, Wu X, Feuk L, Ellison DW, Croul S, et al. Multiple recurrent genetic events converge on control of histone lysine methylation in medulloblastoma. Nat Genet. 2009;41(4):465–72.

    CAS  PubMed  Google Scholar 

  68. Parsons DW, Li M, Zhang X, Jones S, Leary RJ, Lin JC, et al. The genetic landscape of the childhood cancer medulloblastoma. Science. 2011;331(6016):435–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Dubuc AM, Remke M, Korshunov A, Northcott PA, Zhan SH, Mendez-Lago M, et al. Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma. Acta Neuropathol. 2013;125:373–84.

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Korbel JO, Campbell PJ. Criteria for inference of chromothripsis in cancer genomes. Cell. 2013;152(6):1226–36.

    CAS  PubMed  Google Scholar 

  71. Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell. 2011;144(1):27–40.

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Forment JV, Kaidi A, Jackson SP. Chromothripsis and cancer: causes and consequences of chromosome shattering. Nat Rev Cancer. 2012;12(10):663–70.

    CAS  PubMed  Google Scholar 

  73. Kruger R. The role of synphilin-1 in synaptic function and protein degradation. Cell Tissue Res. 2004;318(1):195–9.

    PubMed  Google Scholar 

  74. Eyal A, Engelender S. Synphilin isoforms and the search for a cellular model of lewy body formation in Parkinson’s disease. Cell Cycle. 2006;5(18):2082–6.

    CAS  PubMed  Google Scholar 

  75. Zerbini C, Gelber RD, Weinberg D, Sallan SE, Barnes P, Kupsky W, et al. Prognostic factors in medulloblastoma, including DNA ploidy. J Clin Oncol. 1993;11(4):616–22.

    CAS  PubMed  Google Scholar 

  76. Gajjar AJ, Heideman RL, Douglass EC, Kun LE, Kovnar EH, Sanford RA, et al. Relation of tumor-cell ploidy to survival in children with medulloblastoma. J Clin Oncol. 1993;11(11):2211–7.

    CAS  PubMed  Google Scholar 

  77. Jacobsen PF, Jenkyn DJ, Papadimitriou JM. Establishment of a human medulloblastoma cell line and its heterotransplantation into nude mice. J Neuropathol Exp Neurol. 1985;44(5):472–85.

    CAS  PubMed  Google Scholar 

  78. Friedman HS, Burger PC, Bigner SH, Trojanowski JQ, Wikstrand CJ, Halperin EC, et al. Establishment and characterization of the human medulloblastoma cell line and transplantable xenograft D283 Med. J Neuropathol Exp Neurol. 1985;44(6):592–605.

    CAS  PubMed  Google Scholar 

  79. Friedman HS, Burger PC, Bigner SH, Trojanowski JQ, Brodeur GM, He XM, et al. Phenotypic and genotypic analysis of a human medulloblastoma cell line and transplantable xenograft (D341 Med) demonstrating amplification of c-myc. Am J Pathol. 1988;130(3):472–84.

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Yamada M, Shimizu K, Tamura K, Okamoto Y, Matsui Y, Moriuchi S, et al. [Establishment and biological characterization of human medulloblastoma cell lines]. No To Shinkei. 1989;41(7):695–702.

    CAS  PubMed  Google Scholar 

  81. Pietsch T, Scharmann T, Fonatsch C, Schmidt D, Ockler R, Freihoff D, et al. Characterization of five new cell lines derived from human primitive neuroectodermal tumors of the central nervous system. Cancer Res. 1994;54(12):3278–87.

    CAS  PubMed  Google Scholar 

  82. Milde T, Lodrini M, Savelyeva L, Korshunov A, Kool M, Brueckner LM, et al. HD-MB03 is a novel Group 3 medulloblastoma model demonstrating sensitivity to histone deacetylase inhibitor treatment. J Neurooncol. 2012;110:335–48.

    CAS  PubMed  Google Scholar 

  83. Zhao X, Liu Z, Yu L, Zhang Y, Baxter P, Voicu H, et al. Global gene expression profiling confirms the molecular fidelity of primary tumor-based orthotopic xenograft mouse models of medulloblastoma. Neuro Oncol. 2012;14(5):574–83.

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Gilbertson RJ, Ellison DW. The origins of medulloblastoma subtypes. Annu Rev Pathol. 2008;3:341–65.

    CAS  PubMed  Google Scholar 

  85. Wu X, Northcott PA, Croul S, Taylor MD. Mouse models of medulloblastoma. Chin J Cancer. 2011;30(7):442–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Goodrich LV, Milenkovic L, Higgins KM, Scott MP. Altered neural cell fates and medulloblastoma in mouse patched mutants. Science. 1997;277(5329):1109–13.

    CAS  PubMed  Google Scholar 

  87. Wetmore C, Eberhart DE, Curran T. The normal patched allele is expressed in medulloblastomas from mice with heterozygous germ-line mutation of patched. Cancer Res. 2000;60(8):2239–46.

    CAS  PubMed  Google Scholar 

  88. Wetmore C, Eberhart DE, Curran T. Loss of p53 but not ARF accelerates medulloblastoma in mice heterozygous for patched. Cancer Res. 2001;61(2):513–6.

    CAS  PubMed  Google Scholar 

  89. Hallahan AR, Pritchard JI, Hansen S, Benson M, Stoeck J, Hatton BA, et al. The SmoA1 mouse model reveals that notch signaling is critical for the growth and survival of sonic hedgehog-induced medulloblastomas. Cancer Res. 2004;64(21):7794–800.

    CAS  PubMed  Google Scholar 

  90. Hatton BA, Villavicencio EH, Tsuchiya KD, Pritchard JI, Ditzler S, Pullar B, et al. The Smo/Smo model: hedgehog-induced medulloblastoma with 90% incidence and leptomeningeal spread. Cancer Res. 2008;68(6):1768–76.

    CAS  PubMed  Google Scholar 

  91. Grammel D, Warmuth-Metz M, von Bueren AO, Kool M, Pietsch T, Kretzschmar HA, et al. Sonic hedgehog-associated medulloblastoma arising from the cochlear nuclei of the brainstem. Acta Neuropathol. 2012;123(4):601–14.

    CAS  PubMed  Google Scholar 

  92. Yang ZJ, Ellis T, Markant SL, Read TA, Kessler JD, Bourboulas M, et al. Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell. 2008;14(2):135–45.

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Binning MJ, Niazi T, Pedone CA, Lal B, Eberhart CG, Kim KJ, et al. Hepatocyte growth factor and sonic Hedgehog expression in cerebellar neural progenitor cells costimulate medulloblastoma initiation and growth. Cancer Res. 2008;68(19):7838–45.

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Rao G, Pedone CA, Del Valle L, Reiss K, Holland EC, Fults DW. Sonic hedgehog and insulin-like growth factor signaling synergize to induce medulloblastoma formation from nestin-expressing neural progenitors in mice. Oncogene. 2004;23(36):6156–62.

    CAS  PubMed  Google Scholar 

  95. Doucette TA, Yang Y, Pedone C, Kim JY, Dubuc A, Northcott PD, et al. WIP1 enhances tumor formation in a sonic hedgehog-dependent model of medulloblastoma. Neurosurgery. 2012;70(4):1003–10; discussion 1010.

    PubMed Central  PubMed  Google Scholar 

  96. Marino S, Vooijs M, van Der Gulden H, Jonkers J, Berns A. Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Dev. 2000;14(8):994–1004.

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Lee Y, McKinnon PJ. DNA ligase IV suppresses medulloblastoma formation. Cancer Res. 2002;62(22):6395–9.

    CAS  PubMed  Google Scholar 

  98. Yan CT, Kaushal D, Murphy M, Zhang Y, Datta A, Chen C, et al. XRCC4 suppresses medulloblastomas with recurrent translocations in p53-deficient mice. Proc Natl Acad Sci U S A. 2006;103(19):7378–83.

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Frappart PO, Lee Y, Russell HR, Chalhoub N, Wang YD, Orii KE, et al. Recurrent genomic alterations characterize medulloblastoma arising from DNA double-strand break repair deficiency. Proc Natl Acad Sci U S A. 2009;106(6):1880–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Gibson P, Tong Y, Robinson G, Thompson MC, Currle DS, Eden C, et al. Subtypes of medulloblastoma have distinct developmental origins. Nature. 2010;468(7327):1095–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Kawauchi D, Robinson G, Uziel T, Gibson P, Rehg J, Gao C, et al. A mouse model of the most aggressive subgroup of human medulloblastoma. Cancer Cell. 2012;21(2):168–80.

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Pei Y, Moore CE, Wang J, Tewari AK, Eroshkin A, Cho YJ, et al. An animal model of MYC-driven medulloblastoma. Cancer Cell. 2012;21(2):155–67.

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Swartling FJ, Grimmer MR, Hackett CS, Northcott PA, Fan QW, Goldenberg DD, et al. Pleiotropic role for MYCN in medulloblastoma. Genes Dev. 2010;24(10):1059–72.

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Schwalbe EC, Williamson D, Lindsey JC, Hamilton D, Ryan SL, Megahed H, et al. DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies. Acta Neuropathol. 2013;125(3):359–71.

    CAS  PubMed  Google Scholar 

  105. Hovestadt V, Remke M, Kool M, Pietsch T, Northcott PA, Fischer R, et al. Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumor material using high-density DNA methylation arrays. Acta Neuropathol. 2013;125(6):913–6.

    PubMed Central  PubMed  Google Scholar 

  106. Northcott PA, Shih DJ, Remke M, Cho YJ, Kool M, Hawkins C, et al. Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples. Acta Neuropathol. 2012;123(4):615–26.

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Tabori U, Baskin B, Shago M, Alon N, Taylor MD, Ray PN, et al. Universal poor survival in children with medulloblastoma harboring somatic TP53 mutations. J Clin Oncol. 2010;28(8):1345–50.

    CAS  PubMed  Google Scholar 

  108. Berman DM, Karhadkar SS, Hallahan AR, Pritchard JI, Eberhart CG, Watkins DN, et al. Medulloblastoma growth inhibition by hedgehog pathway blockade. Science. 2002;297(5586):1559–61.

    CAS  PubMed  Google Scholar 

  109. Robarge KD, Brunton SA, Castanedo GM, Cui Y, Dina MS, Goldsmith R, et al. GDC-0449-a potent inhibitor of the hedgehog pathway. Bioorg Med Chem Lett. 2009;19(19):5576–81.

    CAS  PubMed  Google Scholar 

  110. Buonamici S, Williams J, Morrissey M, Wang A, Guo R, Vattay A, et al. Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci Transl Med. 2010;2(51):51ra70.

    PubMed Central  PubMed  Google Scholar 

  111. Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA, Fu L, et al. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Engl J Med. 2009;361(12):1173–8.

    CAS  PubMed  Google Scholar 

  112. Peukert S, He F, Dai M, Zhang R, Sun Y, Miller-Moslin K, et al. Discovery of NVP-LEQ506, a second-generation inhibitor of smoothened. ChemMedChem. 2013;8(8):1261–5.

    CAS  PubMed  Google Scholar 

  113. Yauch RL, Dijkgraaf GJ, Alicke B, Januario T, Ahn CP, Holcomb T, et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science. 2009;326(5952):572–4.

    CAS  PubMed  Google Scholar 

  114. Kim J, Aftab BT, Tang JY, Kim D, Lee AH, Rezaee M, et al. Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists. Cancer Cell. 2013;23(1):23–34.

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Kim J, Lee JJ, Gardner D, Beachy PA. Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector. Proc Natl Acad Sci U S A. 2010;107(30):13432–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Witt O, Milde T, Deubzer HE, Oehme I, Witt R, Kulozik A, et al. Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma or leukemia. Klin Padiatr. 2012;224(6):398–403.

    CAS  PubMed  Google Scholar 

  117. Fouladi M, Park JR, Stewart CF, Gilbertson RJ, Schaiquevich P, Sun J, et al. Pediatric phase I trial and pharmacokinetic study of vorinostat: a Children’s Oncology Group phase I consortium report. J Clin Oncol. 2010;28(22):3623–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  118. Gajjar A, Packer RJ, Foreman NK, Cohen K, Haas-Kogan D, Merchant TE. Children’s Oncology Group’s 2013 blueprint for research: central nervous system tumors. Pediatr Blood Cancer. 2013;60(6):1022–6.

    PubMed Central  PubMed  Google Scholar 

  119. Eberhart C, Brat D, Cohen K, Burger P. Pediatric neuroblastic brain tumors containing abundant neuropil and true rosettes. Pediatr Dev Pathol. 2000;3(4):346–52.

    CAS  PubMed  Google Scholar 

  120. Smoll NR, Drummond KJ. The incidence of medulloblastomas and primitive neurectodermal tumors in adults and children. J Clin Neurosci. 2012;19(11):1541–4.

    PubMed  Google Scholar 

  121. Gandhi R, Babu R, Cummings TJ, Adamson C. Adult primitive neuroectodermal tumors: the prognostic value of supratentorial location. J Neurooncol. 2013;114(1):141–8.

    PubMed  Google Scholar 

  122. Johnston DL, Keene DL, Lafay-Cousin L, Steinbok P, Sung L, Carret AS, et al. Supratentorial primitive neuroectodermal tumors: a Canadian pediatric brain tumor consortium report. J Neurooncol. 2008;86(1):101–8.

    PubMed  Google Scholar 

  123. Fangusaro J, Finlay J, Sposto R, Ji L, Saly M, Zacharoulis S, et al. Intensive chemotherapy followed by consolidative myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) in young children with newly diagnosed supratentorial primitive neuroectodermal tumor (sPNETs): report of the head start I and II experience. Pediatr Blood Cancer. 2008;50(2):312–8.

    PubMed  Google Scholar 

  124. Biswas S, Burke A, Cherian S, Williams D, Nicholson J, Horan G, et al. Non-pineal supratentorial primitive neuro-ectodermal tumors (sPNET) in teenagers and young adults: time to reconsider cisplatin based chemotherapy after cranio-spinal irradiation? Pediatr Blood Cancer. 2009;52(7):796–803.

    PubMed  Google Scholar 

  125. Chintagumpala M, Hassall T, Palmer S, Ashley D, Wallace D, Kasow K, et al. A pilot study of risk-adapted radiotherapy and chemotherapy in patients with supratentorial PNET. Neuro Oncol. 2009;11(1):33–40.

    PubMed Central  PubMed  Google Scholar 

  126. Russo C, Pellarin M, Tingby O, Bollen AW, Lamborn KR, Mohapatra G, et al. Comparative genomic hybridization in patients with supratentorial and infratentorial primitive neuroectodermal tumors. Cancer. 1999;86(2):331–9.

    CAS  PubMed  Google Scholar 

  127. Fan X, Wang Y, Kratz J, Brat DJ, Robitaille Y, Moghrabi A, et al. hTERT gene amplification and increased mRNA expression in central nervous system embryonal tumors. Am J Pathol. 2003;162(6):1763–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  128. McCabe M, Ichimura K, Liu L, Plant K, Backlund L, Pearson D, et al. High-resolution array-based comparative genomic hybridization of medulloblastomas and supratentorial primitive neuroectodermal tumors. J Neuropathol Exp Neurol. 2006;65(6):549–61.

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Pfister S, Remke M, Toedt G, Werft W, Benner A, Mendrzyk F, et al. Supratentorial primitive neuroectodermal tumors of the central nervous system frequently harbor deletions of the CDKN2A locus and other genomic aberrations distinct from medulloblastomas. Genes Chromosomes Cancer. 2007;46(9):839–51.

    CAS  PubMed  Google Scholar 

  130. Miller S, Rogers HA, Lyon P, Rand V, Adamowicz-Brice M, Clifford SC, et al. Genome-wide molecular characterization of central nervous system primitive neuroectodermal tumor and pineoblastoma. Neuro Oncol. 2011;13(8):866–79.

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Li M, Lockwood W, Zielenska M, Northcott P, Ra YS, Bouffet E, et al. Multiple CDK/CYCLIND genes are amplified in medulloblastoma and supratentorial primitive neuroectodermal brain tumor. Cancer Genet. 2012;205(5):220–31.

    CAS  PubMed  Google Scholar 

  132. Behdad A, Perry A. Central nervous system primitive neuroectodermal tumors: a clinicopathologic and genetic study of 33 cases. Brain Pathol. 2010;20(2):441–50.

    PubMed  Google Scholar 

  133. Biegel JA, Fogelgren B, Zhou JY, James CD, Janss AJ, Allen JC, et al. Mutations of the INI1 rhabdoid tumor suppressor gene in medulloblastomas and primitive neuroectodermal tumors of the central nervous system. Clin Cancer Res. 2000;6(7):2759–63.

    CAS  PubMed  Google Scholar 

  134. Gessi M, Gielen GH, Hammes J, Dorner E, Muhlen AZ, Waha A, et al. H3.3 G34R mutations in pediatric primitive neuroectodermal tumors of central nervous system (CNS-PNET) and pediatric glioblastomas: possible diagnostic and therapeutic implications? J Neurooncol. 2013;112(1):67–72.

    CAS  PubMed  Google Scholar 

  135. Balss J, Meyer J, Mueller W, Korshunov A, Hartmann C, von Deimling A. Analysis of the IDH1 codon 132 mutation in brain tumors. Acta Neuropathol. 2008;116(6):597–602.

    CAS  PubMed  Google Scholar 

  136. Hayden JT, Fruhwald MC, Hasselblatt M, Ellison DW, Bailey S, Clifford SC. Frequent IDH1 mutations in supratentorial primitive neuroectodermal tumors (sPNET) of adults but not children. Cell Cycle. 2009;8(11):1806–7.

    CAS  PubMed  Google Scholar 

  137. Gessi M, Setty P, Bisceglia M, zur Muehlen A, Lauriola L, Waha A, et al. Supratentorial primitive neuroectodermal tumors of the central nervous system in adults: molecular and histopathologic analysis of 12 cases. Am J Surg Pathol. 2011;35(4):573–82.

    PubMed  Google Scholar 

  138. Perry A, Miller CR, Gujrati M, Scheithauer BW, Zambrano SC, Jost SC, et al. Malignant gliomas with primitive neuroectodermal tumor-like components: a clinicopathologic and genetic study of 53 cases. Brain Pathol. 2009;19(1):81–90.

    PubMed  Google Scholar 

  139. Koch A, Waha A, Tonn JC, Sorensen N, Berthold F, Wolter M, et al. Somatic mutations of WNT/wingless signaling pathway components in primitive neuroectodermal tumors. Int J Cancer. 2001;93(3):445–9.

    CAS  PubMed  Google Scholar 

  140. Rogers HA, Miller S, Lowe J, Brundler MA, Coyle B, Grundy RG. An investigation of WNT pathway activation and association with survival in central nervous system primitive neuroectodermal tumors (CNS PNET). Br J Cancer. 2009;100(8):1292–302.

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Phi JH, Kim JH, Eun KM, Wang KC, Park KH, Choi SA, et al. Upregulation of SOX2, NOTCH1, and ID1 in supratentorial primitive neuroectodermal tumors: a distinct differentiation pattern from that of medulloblastomas. J Neurosurg Pediatr. 2010;5(6):608–14.

    PubMed  Google Scholar 

  142. Rogers HA, Ward JH, Miller S, Lowe J, Coyle B, Grundy RG. The role of the WNT/beta-catenin pathway in central nervous system primitive neuroectodermal tumors (CNS PNETs). Br J Cancer. 2013;108(10):2130–41.

    CAS  PubMed Central  PubMed  Google Scholar 

  143. Picard D, Miller S, Hawkins CE, Bouffet E, Rogers HA, Chan TS, et al. Markers of survival and metastatic potential in childhood CNS primitive neuro-ectodermal brain tumors: an integrative genomic analysis. Lancet Oncol. 2012;13(8):838–48.

    PubMed Central  PubMed  Google Scholar 

  144. Gessi M, Giangaspero F, Lauriola L, Gardiman M, Scheithauer BW, Halliday W, et al. Embryonal tumors with abundant neuropil and true rosettes: a distinctive CNS primitive neuroectodermal tumor. Am J Surg Pathol. 2009;33(2):211–7.

    PubMed  Google Scholar 

  145. Pfister S, Remke M, Castoldi M, Bai A, Muckenthaler M, Kulozik A, et al. Novel genomic amplification targeting the microRNA cluster at 19q13.42 in a pediatric embryonal tumor with abundant neuropil and true rosettes. Acta Neuropathol. 2009;117(4):457–64.

    CAS  PubMed  Google Scholar 

  146. Li M, Lee KF, Lu Y, Clarke I, Shih D, Eberhart C, et al. Frequent amplification of a chr19q13.41 microRNA polycistron in aggressive primitive neuroectodermal brain tumors. Cancer Cell. 2009;16(6):533–46.

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Korshunov A, Remke M, Gessi M, Ryzhova M, Hielscher T, Witt H, et al. Focal genomic amplification at 19q13.42 comprises a powerful diagnostic marker for embryonal tumors with ependymoblastic rosettes. Acta Neuropathol. 2010;120(2):253–60.

    PubMed  Google Scholar 

  148. Ceccom J, Bourdeaut F, Loukh N, Rigau V, Milin S, Takin R, et al. Embryonal tumor with multilayered rosettes: diagnostic tools update and review of the literature. Clin Neuropathol. 2014;33:15–22.

    PubMed  Google Scholar 

  149. Woehrer A, Slavc I, Peyrl A, Czech T, Dorfer C, Prayer D, et al. Embryonal tumor with abundant neuropil and true rosettes (ETANTR) with loss of morphological but retained genetic key features during progression. Acta Neuropathol. 2011;122(6):787–90.

    PubMed  Google Scholar 

  150. Fuller C, Fouladi M, Gajjar A, Dalton J, Sanford RA, Helton KJ. Chromosome 17 abnormalities in pediatric neuroblastic tumor with abundant neuropil and true rosettes. Am J Clin Pathol. 2006;126(2):277–83.

    PubMed  Google Scholar 

  151. Korshunov A, Ryzhova M, Jones DT, Northcott PA, van Sluis P, Volckmann R, et al. LIN28A immunoreactivity is a potent diagnostic marker of embryonal tumor with multilayered rosettes (ETMR). Acta Neuropathol. 2012;124(6):875–81.

    PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany

    David T. W. Jones & Paul A. Northcott

  2. CCU Neuropathology, German Cancer Research Center (DKFZ), Im Neuenheimer Field 380, Heidelberg, 69120, Germany

    Andrey Korshunov M.D.

  3. Department of Pediatric Neurooncology, Deutsches Kresbsforschungszentrum, University Hospital Heidelberg, Im Neuenheimer Feld 280, Heidelberg, 69120, Germany

    Stefan M. Pfister M.D.

  4. Department of Surgery, Division of Neurosurgery and Labatt Brain Tumor Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, 555 University Avenue, Hill 1503, Toronto, ON, Canada, M5G 1X8

    Michael D. Taylor

  5. Department of Laboratory Medicine and Pathobiology, University of Toronto, Medical Sciences Buildings, 1 King’s College Circle, 6th Floor, Toronto, ON, Canada, M5S 1A8

    Michael D. Taylor

Authors
  1. David T. W. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrey Korshunov M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Stefan M. Pfister M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael D. Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Paul A. Northcott
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul A. Northcott .

Editor information

Editors and Affiliations

  1. Associate Professor of Pediatrics and Otolaryngology, NYU Langone Medical Center, New York, New York, USA

    Matthias A. Karajannis

  2. Professor of Pathology and Neurosurgery, NYU Langone Medical Center, New York, New York, USA

    David Zagzag

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer Science+Business Media New York

About this chapter

Cite this chapter

Jones, D.T.W., Korshunov, A., Pfister, S.M., Taylor, M.D., Northcott, P.A. (2015). Medulloblastoma and CNS Primitive Neuroectodermal Tumors. In: Karajannis, M., Zagzag, D. (eds) Molecular Pathology of Nervous System Tumors. Molecular Pathology Library, vol 8. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-1830-0_9

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-1830-0_9

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4939-1829-4

  • Online ISBN: 978-1-4939-1830-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation