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Acta Neuropathologica

, Volume 129, Issue 3, pp 449–457 | Cite as

Medulloblastoma subgroups remain stable across primary and metastatic compartments

  • Xin Wang
  • Adrian M. Dubuc
  • Vijay Ramaswamy
  • Stephen Mack
  • Deena M. A. Gendoo
  • Marc Remke
  • Xiaochong Wu
  • Livia Garzia
  • Betty Luu
  • Florence Cavalli
  • John Peacock
  • Borja López
  • Patryk Skowron
  • David Zagzag
  • David Lyden
  • Caitlin Hoffman
  • Yoon-Jae Cho
  • Charles Eberhart
  • Tobey MacDonald
  • Xiao-Nan Li
  • Timothy Van Meter
  • Paul A. Northcott
  • Benjamin Haibe-Kains
  • Cynthia Hawkins
  • James T. Rutka
  • Eric Bouffet
  • Stefan M. Pfister
  • Andrey Korshunov
  • Michael D. Taylor
Original Paper

Abstract

Medulloblastoma comprises four distinct molecular variants with distinct genetics, transcriptomes, and outcomes. Subgroup affiliation has been previously shown to remain stable at the time of recurrence, which likely reflects their distinct cells of origin. However, a therapeutically relevant question that remains unanswered is subgroup stability in the metastatic compartment. We assembled a cohort of 12-paired primary-metastatic tumors collected in the MAGIC consortium, and established their molecular subgroup affiliation by performing integrative gene expression and DNA methylation analysis. Frozen tissues were collected and profiled using Affymetrix gene expression arrays and Illumina methylation arrays. Class prediction and hierarchical clustering were performed using existing published datasets. Our molecular analysis, using consensus integrative genomic data, establishes the unequivocal maintenance of molecular subgroup affiliation in metastatic medulloblastoma. We further validated these findings by interrogating a non-overlapping cohort of 19 pairs of primary-metastatic tumors from the Burdenko Neurosurgical Institute using an orthogonal technique of immunohistochemical staining. This investigation represents the largest reported primary-metastatic paired cohort profiled to date and provides a unique opportunity to evaluate subgroup-specific molecular aberrations within the metastatic compartment. Our findings further support the hypothesis that medulloblastoma subgroups arise from distinct cells of origin, which are carried forward from ontogeny to oncology.

Keywords

Medulloblastoma Metastasis Molecular subgroups Integrative genomics Gene expression DNA methylation 

Notes

Acknowledgments

XW is supported by a CIHR Vanier Canada Graduate Scholarship, McLaughlin Centre for Molecular Medicine MD/PhD Scholarship, and the Ruggles MD/PhD Innovation Award. MDT is supported by a CIHR Clinician Scientist Phase II award, funds from the Garron Family Chair in Childhood Cancer Research at The Hospital for Sick Children and The University of Toronto, and operating funds from the Canadian Institutes of Health Research, the National Institutes of Health (R01CA159859 and R01CA148699) and the Pediatric Brain Tumor Foundation. VR is supported by a CIHR fellowship, an Alberta Innovates-Health Solutions Clinical Fellowship and a Young Investigator Award from Alex’s Lemonade Stand Foundation. BHK is supported by the Gattuso-Slaight Personalized Cancer Medicine Fund at the Princess Margaret Cancer Centre. We wish to acknowledge the Labatt Brain Tumour Research Centre and Tumour Tissue Repository, which are supported by b.r.a.i.n.child and Meagan’s Walk.

Supplementary material

401_2015_1389_MOESM1_ESM.eps (1.5 mb)
Supplementary material 1 (EPS 1542 kb) Supplementary Fig. 1 PCA of the primary and metastatic medulloblastoma samples described in using the 1,000 most differentially expressed genes (a) and 10,000 most differentially methylated probes (b). Coloured ellipsoids (red = SHH, yellow = Group 3, green = Group 4) represent 1.5 SDs of the data distribution for each subgroup. Individual patients are indicated with a unique colour
401_2015_1389_MOESM2_ESM.docx (26 kb)
Supplementary material 2 (DOCX 25 kb) Supplementary Table 1. Medulloblastoma subgroup predictions and consensus using integrative genomics analysis based on gene expression and 450k DNA methylation
401_2015_1389_MOESM3_ESM.xlsx (61 kb)
Supplementary material 3 (XLSX 60 kb) Supplementary Table 2. Detailed demographic, clinical, and histological characteristics of patients

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Xin Wang
    • 1
    • 2
  • Adrian M. Dubuc
    • 1
    • 2
  • Vijay Ramaswamy
    • 1
    • 2
    • 3
  • Stephen Mack
    • 1
    • 2
  • Deena M. A. Gendoo
    • 4
  • Marc Remke
    • 1
    • 2
  • Xiaochong Wu
    • 1
  • Livia Garzia
    • 1
  • Betty Luu
    • 1
  • Florence Cavalli
    • 1
  • John Peacock
    • 1
    • 2
  • Borja López
    • 1
  • Patryk Skowron
    • 1
    • 2
  • David Zagzag
    • 5
  • David Lyden
    • 6
  • Caitlin Hoffman
    • 1
    • 7
  • Yoon-Jae Cho
    • 8
  • Charles Eberhart
    • 9
  • Tobey MacDonald
    • 10
  • Xiao-Nan Li
    • 11
  • Timothy Van Meter
    • 12
  • Paul A. Northcott
    • 13
  • Benjamin Haibe-Kains
    • 4
    • 14
  • Cynthia Hawkins
    • 15
  • James T. Rutka
    • 7
  • Eric Bouffet
    • 3
  • Stefan M. Pfister
    • 13
  • Andrey Korshunov
    • 16
  • Michael D. Taylor
    • 1
    • 7
  1. 1.Developmental and Stem Cell Biology Program, The Hospital for Sick ChildrenUniversity of TorontoTorontoCanada
  2. 2.Department of Laboratory Medicine and PathobiologyUniversity of TorontoTorontoCanada
  3. 3.Division of Haematology/OncologyHospital for Sick ChildrenTorontoCanada
  4. 4.Bioinformatics and Computational Genomics Laboratory, Princess Margaret Cancer CentreUniversity Health NetworkTorontoCanada
  5. 5.Departments of Pathology and NeurosurgeryNYU Langone Medical CenterNew YorkUSA
  6. 6.Departments of Pediatrics, Cell and Developmental BiologyWeill Medical College of Cornell UniversityNew YorkUSA
  7. 7.Division of NeurosurgeryHospital for Sick ChildrenTorontoCanada
  8. 8.Department of Neurology and Neurological SciencesStanford University School of MedicineStanfordUSA
  9. 9.Departments of Pathology, Ophthalmology and OncologyJohn Hopkins University School of MedicineBaltimoreUSA
  10. 10.Pediatric Neuro-Oncology ProgramEmory University School of MedicineAtlantaUSA
  11. 11.Department of Pediatrics, Brain Tumor Program, Children’s Cancer CenterBaylor College of MedicineHoustonUSA
  12. 12.Department of PediatricsVirginia Commonwealth University School of MedicineRichmondUSA
  13. 13.Division of Pediatric Neurooncology, Department of Pediatric Hematology and Oncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ)Heidelberg University HospitalHeidelbergGermany
  14. 14.Department of Medical BiophysicsUniversity of TorontoTorontoCanada
  15. 15.Department of PathologyHospital for Sick ChildrenTorontoCanada
  16. 16.Clinical Cooperation Unit NeuropathologyGerman Cancer Research Center (DKFZ)HeidelbergGermany

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