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Subgroup and subtype-specific outcomes in adult medulloblastoma

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Abstract

Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0–86.5), 61.9% (51.6–74.2), 80.0% (95% CI 51.6–100.0), and 44.9% (95% CI 28.6–70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1–7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3–9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1–4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1–6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1–0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed.

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Acknowledgements

HC was supported by a Garron Family Cancer Centre Research Fellowship. MDT is supported by operating funds from the National Institutes for Health (5R01CA159859-08 and R01NS106155-01) and the Pediatric Brain Tumor Foundation. V.R. and M.D.T. are supported by a Stand Up To Cancer (SU2C) St. Baldrick’s Pediatric Dream Team translational research grant (SU2C-AACR-DT1113). VR is supported by operating funds from the Canadian Institutes for Health Research, the Canadian Cancer Society Research Institute, the C.R. Younger Foundation, the Garron Family Cancer Centre, Meagan’s Walk, b.r.a.i.n.child and Nelina’s Hope. This study was partially funded with support provided by the Government of Ontario, Ministry of Research, Innovation and Science, and the Princess Margaret Cancer Foundation and support from the Princess Margaret Cancer Centre-OICR Translational Genomics Laboratory. EGVM is supported by operating funds from the National Institutes of Health (R01NS096236 and R01CA235162).

Author information

Author notes

  1. Paul A. Northcott, Andrey Korshunov and Vijay Ramaswamy have contributed equally to this manuscript.

Authors and Affiliations

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

    Hallie Coltin & Vijay Ramaswamy

  2. Programme in Developmental and Stem Cell Biology, Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON, Canada

    Hallie Coltin, Lakshmikirupa Sundaresan, Patryk Skowron, Michael D. Taylor & Vijay Ramaswamy

  3. Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, MS 325, Room D2058, 262 Danny Thomas Place, Memphis, TN, 38105-3678, USA

    Kyle S. Smith & Paul A. Northcott

  4. Department of Neurosurgery, Fondazione Policlinico A. Gemelli IRCCS, Catholic University Medical School, Rome, Italy

    Luca Massimi

  5. Department of Neuropathology and Ophthalmic Pathology, Johns Hopkins University, Baltimore, MD, USA

    Charles G. Eberhart

  6. Department of Neurology, Johns Hopkins University, Baltimore, MD, USA

    Karisa C. Schreck

  7. Departments of Neurological Surgery and Pediatrics, University of California, San Francisco, CA, USA

    Nalin Gupta

  8. Departments of Neurology, Neurological Surgery, and Pediatrics, University of California, San Francisco, CA, USA

    William A. Weiss

  9. Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, University of Sao Paulo, São Paulo, Brazil

    Daniela Tirapelli & Carlos Carlotti

  10. Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong

    Kay K. W. Li

  11. NN Burdenko Neurosurgical Research Centre, Moscow, Russia

    Marina Ryzhova, Andrey Golanov, Olga Zheludkova & Oksana Absalyamova

  12. Hopp Children’s Cancer Center Heidelberg (KiTZ) and Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany

    Konstantin Okonechnikov, Stefan M. Pfister & Marcel Kool

  13. Clinical Cooperation Unit Neuropathology (B300), German Cancer Research Center (DKFZ) and Department of Neuropathology, University of Heidelberg, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120, Heidelberg, Germany

    Damian Stichel, Andreas von Deimling & Andrey Korshunov

  14. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Caterina Giannini

  15. Center for Cancer and Blood Disorders, Children’s National Medical Center, Washington, DC, USA

    Scott Raskin & Roger J. Packer

  16. Department of Neurosurgery, O’Neal Comprehensive Cancer Center, University of Alabama at Birmingham (UAB), Birmingham, AL, USA

    Erwin G. Van Meir

  17. Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada

    Jennifer A. Chan

  18. Department of Neurosurgery, University of Utah, Salt Lake City, UT, USA

    Daniel Fults

  19. Department of Neurological Surgery, Vanderbilt Medical Center, Nashville, TN, USA

    Lola B. Chambless

  20. Department of Neurosurgery, Division of Pediatric Neurosurgery, Seoul National University Children’s Hospital, Seoul, South Korea

    Seung-Ki Kim

  21. Centre de Pathologie et Neuropathologie Est, Centre de Biologie et Pathologie Est, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France

    Alexandre Vasiljevic

  22. ONCOFLAM, Neuro-Oncologie Et Neuro-Inflammation Centre de Recherche en Neurosciences de Lyon, Lyon, France

    Alexandre Vasiljevic

  23. Department of Pediatrics, Institut d’Hemato-Oncologie Pediatrique, Lyon, France

    Cecile Faure-Conter

  24. Department of Pediatrics, University of Colorado Denver, Aurora, CO, USA

    Rajeev Vibhakar

  25. Department of Neurosurgery, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital and Medical School, Hwasun-gun, Chonnam, South Korea

    Shin Jung

  26. Cancer and Blood Disorders Center, Seattle Children’s Hospital, Seattle, WA, USA

    Sarah Leary

  27. Developmental Tumor Biology Laboratory, Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain

    Jaume Mora

  28. Department of Pathology, Duke University, Durham, NC, USA

    Roger E. McLendon

  29. Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Ian F. Pollack

  30. 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary

    Peter Hauser

  31. Department of Pathology, The Children’s Memorial Health Institute, Warsaw, Poland

    Wieslawa A. Grajkowska

  32. Departments of Pediatrics, Anatomy and Neurobiology, Washington University School of Medicine and St Louis Children’s Hospital, St Louis, MO, USA

    Joshua B. Rubin

  33. Department of Neurosurgery, Brain Tumour Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

    Marie-Lise C. van Veelen

  34. Department of Neurology, Brain Tumour Center, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

    Pim J. French

  35. Department of Pathology, Erasmus University Medical Center, Rotterdam, Netherlands

    Johan M. Kros

  36. Department of Neurosurgery, David Geffen School of Medicine at University of California at Los Angeles, University of California Los Angeles, Los Angeles, CA, 90095, USA

    Linda M. Liau

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

    Stefan M. Pfister

  38. Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands

    Marcel Kool

  39. Department of Neurosurgery, Osaka University Graduate School of Medicine, Suita, Japan

    Noriyuki Kijima

  40. Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    Vijay Ramaswamy

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Contributions

Experimental design: HC and VR; data collection—all authors; data analysis: HC, LS, KSS, PAN, AK, and VR; interpretation of the data—all authors; funding: VR and MDT; manuscript writing: HC and VR.

Corresponding authors

Correspondence to Paul A. Northcott, Andrey Korshunov or Vijay Ramaswamy.

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401_2021_2358_MOESM1_ESM.xlsx

Supplementary file1 Online Table 1: Clinical characteristics of 191 adult medulloblastoma patients. Online Table 2: Clinical characteristics of the 25 adult Group 4 validation patients. Online Table 3: Clinical characteristics of the 62 pediatric Group 4 medulloblastoma. (XLSX 33 KB)

Supplementary file2 (PDF 2347 KB)

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Coltin, H., Sundaresan, L., Smith, K.S. et al. Subgroup and subtype-specific outcomes in adult medulloblastoma. Acta Neuropathol 142, 859–871 (2021). https://doi.org/10.1007/s00401-021-02358-4

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