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Biological and clinical heterogeneity of MYCN-amplified medulloblastoma

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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.

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Acknowledgments

This study was supported by a grant from the Deutsche Kinderkrebsstiftung to S.P., a “Lina Marguerite Siebert” Award, a “Young Investigator Fellowship” of the Medical Faculty of Heidelberg and a grant from the Landesstiftung Baden-Wuerttemberg to M.R., and a guest scientist fellowship of the German Cancer Research Center (DKFZ) Heidelberg to M.Ry., EU (FP6 and FP7): E.E.T. Pipeline #037260 and ASSET #259348 to F.W..

Conflict of interest

The authors declare no conflicts of interest.

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Authors and Affiliations

  1. Department of Neuropathology, University of Heidelberg, Heidelberg, Germany

    Andrey Korshunov & Andreas von Deimling

  2. Clinical Cooperation Unit Neuropathology, German Cancer Research Center, Heidelberg, Germany

    Andrey Korshunov & Andreas von Deimling

  3. Division Molecular Genetics, German Cancer Research Center, Heidelberg, Germany

    Marc Remke, Marcel Kool, Elke Pfaff, Hendrik Witt, David T. W. Jones, Andrea Wittmann, Peter Lichter & Stefan M. Pfister

  4. Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany

    Marc Remke, Hendrik Witt, Andreas E. Kulozik & Stefan M. Pfister

  5. Division Biostatistics, German Cancer Research Center, Heidelberg, Germany

    Thomas Hielscher & Axel Benner

  6. Program in Developmental and Stem Cell Biology, Division of Neurosurgery, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, Canada

    Paul A. Northcott & Michael D. Taylor

  7. Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK

    Dan Williamson & Steven C. Clifford

  8. NN Burdenko Neurosurgical Institute, Moscow, Russia

    Marina Ryzhova

  9. Children’s Hospital Boston, Boston, USA

    Yoon-Jae Cho

  10. Departments of Neurology, Pediatrics, and Neurological Surgery, UCSF, San Francisco, USA

    William A. Weiss

  11. Cnopf’sche Kinderklinik, Nürnberg Children’s Hospital, Nürnberg, Germany

    Wolfram Scheurlen

  12. Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, UK

    V. Peter Collins

  13. Division Tumor Genetics, German Cancer Research Center, Heidelberg, Germany

    Frank Westermann

  14. Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Stefan M. Pfister

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  1. Andrey Korshunov
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Correspondence to Stefan M. Pfister.

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Supplementary Table 1 (DOCX 24 kb)

401_2011_918_MOESM2_ESM.eps

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

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

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

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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Korshunov, A., Remke, M., Kool, M. et al. Biological and clinical heterogeneity of MYCN-amplified medulloblastoma. Acta Neuropathol 123, 515–527 (2012). https://doi.org/10.1007/s00401-011-0918-8

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  • DOI: https://doi.org/10.1007/s00401-011-0918-8

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