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Risk stratification of childhood medulloblastoma in the molecular era: the current consensus

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Abstract

Historical risk stratification criteria for medulloblastoma rely primarily on clinicopathological variables pertaining to age, presence of metastases, extent of resection, histological subtypes and in some instances individual genetic aberrations such as MYC and MYCN amplification. In 2010, an international panel of experts established consensus defining four main subgroups of medulloblastoma (WNT, SHH, Group 3 and Group 4) delineated by transcriptional profiling. This has led to the current generation of biomarker-driven clinical trials assigning WNT tumors to a favorable prognosis group in addition to clinicopathological criteria including MYC and MYCN gene amplifications. However, outcome prediction of non-WNT subgroups is a challenge due to inconsistent survival reports. In 2015, a consensus conference was convened in Heidelberg with the objective to further refine the risk stratification in the context of subgroups and agree on a definition of risk groups of non-infant, childhood medulloblastoma (ages 3–17). Published and unpublished data over the past 5 years were reviewed, and a consensus was reached regarding the level of evidence for currently available biomarkers. The following risk groups were defined based on current survival rates: low risk (>90 % survival), average (standard) risk (75–90 % survival), high risk (50–75 % survival) and very high risk (<50 % survival) disease. The WNT subgroup and non-metastatic Group 4 tumors with whole chromosome 11 loss or whole chromosome 17 gain were recognized as low-risk tumors that may qualify for reduced therapy. High-risk strata were defined as patients with metastatic SHH or Group 4 tumors, or MYCN-amplified SHH medulloblastomas. Very high-risk patients are Group 3 with metastases or SHH with TP53 mutation. In addition, a number of consensus points were reached that should be standardized across future clinical trials. Although we anticipate new data will emerge from currently ongoing and recently completed clinical trials, this consensus can serve as an outline for prioritization of certain molecular subsets of tumors to define and validate risk groups as a basis for future clinical trials.

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    Authors and Affiliations

    1. Division of Haematology/Oncology, Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5G 1X8, Canada

      Vijay Ramaswamy & Eric Bouffet

    2. Department of Pediatric Oncology, Hematology, and Clinical Immunology, University Hospital Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany

      Marc Remke

    3. Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Düsseldorf, Germany

      Marc Remke

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

      Simon Bailey & Steven C. Clifford

    5. Department of Paediatric, Adolescents and Young Adults Oncology, Curie Institute, and University Paris Descartes, Paris, France

      Francois Doz

    6. Division of Pediatric Neurooncology (B062), DKFZ, and German Cancer Consortium (DKTK), Heidelberg, Germany

      Marcel Kool & Stefan M. Pfister

    7. Department of Pediatric and Adolescent Oncology, Institut Gustave-Roussy, Villejuif, France

      Christelle Dufour & Gilles Vassal

    8. Department of Pediatric Oncology, Hematology and Clinical Immunology, University Hospital Heidelberg, Heidelberg, Germany

      Till Milde, Olaf Witt & Stefan M. Pfister

    9. Clinical Cooperation Unit Pediatric Oncology (G340), DKFZ, Heidelberg, Germany

      Till Milde & Olaf Witt

    10. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

      Katja von Hoff & Stefan Rutkowski

    11. Neuropathology, University of Bonn, Bonn, Germany

      Torsten Pietsch

    12. St. Jude’s Research Hospital, Memphis, TN, USA

      Paul A. Northcott, Amar Gajjar & Giles W. Robinson

    13. Aix-Marseille Université, Inserm, CRO2 UMR_S 911, 27 bd Jean Moulin, 13385, Marseille Cedex 05, France

      Laetitia Padovani

    14. Department of Pediatric Hematology and Oncology, AP-HM, Marseille, France

      Nicolas André

    15. Fondazione IRCCS “Istituto Nazionale dei Tumori”, Milan, Italy

      Maura Massimino

    16. Department of Oncology, Alder Hey Children’s NHS Foundation Trust, Liverpool, UK

      Barry Pizer

    17. Department of Neurology, Children’s National Medical Center, Washington, DC, USA

      Roger Packer

    18. Division of Neurosurgery, Hospital for Sick Children, Toronto, ON, Canada

      Michael D. Taylor

    19. Department of Neurology, Boston Children’s Hospital and Harvard Medical School, Boston, MA, USA

      Scott L. Pomeroy

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    Correspondence to Vijay Ramaswamy or Marc Remke.

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    V. Ramaswamy and M. Remke contributed equally to this work.

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    Ramaswamy, V., Remke, M., Bouffet, E. et al. Risk stratification of childhood medulloblastoma in the molecular era: the current consensus. Acta Neuropathol 131, 821–831 (2016). https://doi.org/10.1007/s00401-016-1569-6

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    • DOI: https://doi.org/10.1007/s00401-016-1569-6

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