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Expression profiling of ependymomas unravels localization and tumor grade-specific tumorigenesis

  1. Thomas Palm ChE1,
  2. Dominique Figarella-Branger MD, PhD2,
  3. Françoise Chapon MD, PhD3,
  4. Catherine Lacroix MD4,
  5. Françoise Gray MD, PhD5,
  6. Francesco Scaravilli MD, PhD6,
  7. David W. Ellison MD, PhD7,
  8. Isabelle Salmon MD, PhD8,
  9. Miikka Vikkula MD, PhD1,†,
  10. Catherine Godfraind MD, PhD9,†,‡,*

Article first published online: 17 JUN 2009

DOI: 10.1002/cncr.24476

Issue

Cancer

Cancer

Volume 115, Issue 17, pages 3955–3968, 1 September 2009

Additional Information

How to Cite

Palm, T., Figarella-Branger, D., Chapon, F., Lacroix, C., Gray, F., Scaravilli, F., Ellison, D. W., Salmon, I., Vikkula, M. and Godfraind, C. (2009), Expression profiling of ependymomas unravels localization and tumor grade-specific tumorigenesis. Cancer, 115: 3955–3968. doi: 10.1002/cncr.24476

Author Information

  1. 1

    Laboratory of Human Molecular Genetics, Duve Institute, Catholic University of Louvain, Brussels, Belgium

  2. 2

    Department of Pathology and Neuropathology, La Timone's Hospital, AP-HM and EA3281, University of the Mediterranean, Marseille, France

  3. 3

    Laboratory of Pathology, CHU-Caen, Caen, France

  4. 4

    Laboratory of Pathology, Hôpital Kremlin-Bicêtre, Paris, France

  5. 5

    Department of Pathology, APHP Hôpital Lariboisière, Université Paris VII, Paris, France

  6. 6

    Department of Neuropathology, Institute of Neurology, Queen Square, University College London, London, United Kingdom

  7. 7

    Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee

  8. 8

    Laboratory of Pathology, Erasmus University Hospital, Free University of Brussels, Brussels, Belgium

  9. 9

    Neuroscience Center, Laboratory of Neuropathology, Catholic University of Louvain, Brussels, Belgium

  1. †

    The last 2 authors contributed equally to this work.

  2. ‡

    Fax: (011) 32-2-764-74-60

*Laboratory of Pathology, Cliniques Universitaires St. Luc, Université Catholique de Louvain, Avenue Hippocrate, 10, 1200 Brussels, Belgium

Publication History

  1. Issue published online: 20 AUG 2009
  2. Article first published online: 17 JUN 2009
  3. Manuscript Accepted: 5 FEB 2009
  4. Manuscript Revised: 13 JAN 2009
  5. Manuscript Received: 17 SEP 2008

Funded by

  • Fonds Maisin (UCL)
  • Fédération belge contre le cancer
  • Fonds pour la formation á la recherche dans l'industrie et l'agriculture

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Keywords:

  • ependymoma;
  • expression profiling;
  • gene signature;
  • tumorigenesis;
  • pathways;
  • microarray

By analyzing microarray-based expression profiles of a series of frozen ependymomas, the authors defined gene signatures specific to tumor localization and to World Health Organization grades. On the basis of these signatures, the authors related dysregulation of developmental—stem cell controlling—pathways to tumor localization, and the Wnt/β-catenin signaling pathway and several of its downstream or interacting pathways to anaplastic ependymomas.

Abstract

BACKGROUND:

Ependymomas derive from ependymal cells that cover the cerebral ventricles and the central canal of the spinal cord. The molecular alterations leading to ependymomal oncogenesis are not completely understood.

METHODS:

The authors performed array-based expression profiling on a series of 34 frozen ependymal tumors with different localizations and histologic grades. Data were analyzed by nonsupervised and supervised clustering methods along with Gene Ontology and Pathway Analyzer tools.

RESULTS:

Class discovery experiments indicated a strong correlation between profiles and tumor localization as well as World Health Organization (WHO) tumor grades. On the basis of supervised clustering, intracranial ependymomas were associated with high expression levels of Notch, Hedgehog, and bone morphogenetic protein pathway members. In contrast, most of the homeobox-containing genes manifested high expression in extracranial ependymomas. The results also revealed that WHO grade 2 ependymomas differed from WHO grade 3 ependymomas by genes implicated in Wnt/β-catenin signaling, cell cycle, E2F transcription factor 1 destruction, angiogenesis, apoptosis, remodeling of adherens junctions, and mitotic spindle formation.

CONCLUSIONS:

Taken together, the tumor localization-related gene sets mainly implicated in stem cell maintenance, renewal, and differentiation suggest the dysregulation of localized cancer stem cells during ependymoma development. The WHO grade differentiating pathways suggested that alteration of the Wnt/β-catenin signaling pathway is a key event in the tumorigenesis of WHO grade 3 ependymomas. On the basis of the current data, the authors suggest a developmental scheme of ependymomas that integrates tumor localization and tumor grades, and that pinpoints new targets for the development of future therapeutic approaches. Cancer 2009. © 2009 American Cancer Society.

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