Acta Neuropathologica

, Volume 123, Issue 4, pp 515–527 | Cite as

Biological and clinical heterogeneity of MYCN-amplified medulloblastoma

  • Andrey Korshunov
  • Marc Remke
  • Marcel Kool
  • Thomas Hielscher
  • Paul A. Northcott
  • Dan Williamson
  • Elke Pfaff
  • Hendrik Witt
  • David T. W. Jones
  • Marina Ryzhova
  • Yoon-Jae Cho
  • Andrea Wittmann
  • Axel Benner
  • William A. Weiss
  • Andreas von Deimling
  • Wolfram Scheurlen
  • Andreas E. Kulozik
  • Steven C. Clifford
  • V. Peter Collins
  • Frank Westermann
  • Michael D. Taylor
  • Peter Lichter
  • Stefan M. Pfister
Original Paper

Abstract

Focal high-level amplifications of MYC (or MYCC) define a subset of high-risk medulloblastoma patients. However, the prognostic role of MYCN oncogene amplification remains unresolved. We aimed to evaluate the prognostic value of this alteration alone and in combination with biological modifiers in 67 pediatric medulloblastomas with MYCN amplification (MYCN-MB). Twenty-one MYCN-MB were examined using gene expression profiling and array-CGH, whereas for 46 tumors immunohistochemical analysis and FISH were performed. All 67 tumors were further subjected to mutational analyses. We compared molecular, clinical, and prognostic characteristics both within biological MYCN-MB groups and with non-amplified tumors. Transcriptomic analysis revealed SHH-driven tumorigenesis in a subset of MYCN-MBs indicating a biological dichotomy of MYCN-MB. Activation of SHH was accompanied by variant-specific cytogenetic aberrations including deletion of 9q in SHH tumors. Non-SHH MB were associated with gain of 7q and isochromosome 17q/17q gain. Among clinically relevant variables, SHH subtype and 10q loss for non-SHH tumors comprised the most powerful markers of favorable prognosis in MYCN-MB. In conclusion, we demonstrate considerable heterogeneity within MYCN-MB in terms of genetics, tumor biology, and clinical outcome. Thus, assessment of disease group and 10q copy-number status may improve risk stratification of this group and may delineate MYCN-MB with the same dismal prognosis as MYC amplified tumors. Furthermore, based on the enrichment of MYCN and GLI2 amplifications in SHH-driven medulloblastoma, amplification of these downstream signaling intermediates should be taken into account before a patient is enrolled into a clinical trial using a smoothened inhibitor.

Keywords

MYCN SHH pathway 10q loss Medulloblastoma 

Supplementary material

401_2011_918_MOESM1_ESM.docx (23 kb)
Supplementary Table 1 (DOCX 24 kb)
401_2011_918_MOESM2_ESM.eps (4.5 mb)
Unsupervised hierarchical clustering from 77 primary medulloblastomas using 300 genes with high standard deviation demonstrates the presence of MYCN amplifications in various subgroups. Molecular characteristics (amplifications of MYCN, MYC (red), and GLI2; 6q loss, gain of chromosome 7, loss of 9q, 10q, and 17p; gain of 17q; disease variant denominations: WNT (blue), SHH (red), group C (yellow), and group D (green)) of the study population are shown below the dendrogram. Molecular alteration present (black). (EPS 4643 kb)
401_2011_918_MOESM3_ESM.docx (417 kb)
a Bootstrapped ARACNE network illustrating the estimated interacting genes in 77 primary medulloblastomas. Limited subnetwork shown to illustrate an estimated direct interaction between MYCN and the SHH-specific gene GLI2. b Expression of GLI2 (left panel) and MYCN (right panel) transcripts derived from transcriptome analysis of primary medulloblastoma, grouped according to the presence of MYCN amplification and/or SHH pathway activation. (DOCX 417 kb)
401_2011_918_MOESM4_ESM.eps (1.6 mb)
Kaplan-Meier plot of estimated overall survival time (a) and progression-free survival time (b) distributions. The number of patients under risk is indicated for time increments of 12 months. Kaplan-Meier plots according to the presence MYCN amplification in tumors with SHH pathway activation (EPS 1599 kb)
401_2011_918_MOESM5_ESM.eps (1.9 mb)
Kaplan-Meier plot of estimated overall survival time (a) and progression-free survival time (b) distributions. The number of patients under risk is indicated for time increments of 12 months. Kaplan-Meier plots according to the presence MYCN amplification in non-SHH medulloblastomas (EPS 1947 kb)

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Andrey Korshunov
    • 1
    • 2
  • Marc Remke
    • 3
    • 4
  • Marcel Kool
    • 3
  • Thomas Hielscher
    • 5
  • Paul A. Northcott
    • 6
  • Dan Williamson
    • 7
  • Elke Pfaff
    • 3
  • Hendrik Witt
    • 3
    • 4
  • David T. W. Jones
    • 3
  • Marina Ryzhova
    • 8
  • Yoon-Jae Cho
    • 9
  • Andrea Wittmann
    • 3
  • Axel Benner
    • 5
  • William A. Weiss
    • 10
  • Andreas von Deimling
    • 1
    • 2
  • Wolfram Scheurlen
    • 11
  • Andreas E. Kulozik
    • 4
  • Steven C. Clifford
    • 7
  • V. Peter Collins
    • 12
  • Frank Westermann
    • 13
  • Michael D. Taylor
    • 6
  • Peter Lichter
    • 3
  • Stefan M. Pfister
    • 3
    • 4
    • 14
  1. 1.Department of NeuropathologyUniversity of HeidelbergHeidelbergGermany
  2. 2.Clinical Cooperation Unit NeuropathologyGerman Cancer Research CenterHeidelbergGermany
  3. 3.Division Molecular GeneticsGerman Cancer Research CenterHeidelbergGermany
  4. 4.Department of Pediatric Oncology, Hematology and ImmunologyUniversity of HeidelbergHeidelbergGermany
  5. 5.Division BiostatisticsGerman Cancer Research CenterHeidelbergGermany
  6. 6.Program in Developmental and Stem Cell Biology, Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick ChildrenUniversity of TorontoTorontoCanada
  7. 7.Northern Institute for Cancer ResearchNewcastle UniversityNewcastle upon TyneUK
  8. 8.NN Burdenko Neurosurgical InstituteMoscowRussia
  9. 9.Children’s Hospital BostonBostonUSA
  10. 10.Departments of Neurology, Pediatrics, and Neurological SurgeryUCSFSan FranciscoUSA
  11. 11.Cnopf’sche KinderklinikNürnberg Children’s HospitalNürnbergGermany
  12. 12.Division of Molecular Histopathology, Department of PathologyUniversity of CambridgeCambridgeUK
  13. 13.Division Tumor GeneticsGerman Cancer Research CenterHeidelbergGermany
  14. 14.HeidelbergGermany

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