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Letters to Nature

Nature 415, 436-442 (24 January 2002) | doi:10.1038/415436a; Received 18 July 2001; Accepted 13 November 2001

Prediction of central nervous system embryonal tumour outcome based on gene expression

Scott L. Pomeroy1, Pablo Tamayo2, Michelle Gaasenbeek2, Lisa M. Sturla1, Michael Angelo2, Margaret E. McLaughlin3, John Y. H. Kim1,4, Liliana C. Goumnerova5, Peter M. Black5, Ching Lau6, Jeffrey C. Allen7, David Zagzag8, James M. Olson9, Tom Curran10, Cynthia Wetmore10, Jaclyn A. Biegel11, Tomaso Poggio12, Shayan Mukherjee12, Ryan Rifkin12, Andrea Califano13, Gustavo Stolovitzky13, David N. Louis14, Jill P. Mesirov2, Eric S. Lander2,15 & Todd R. Golub2,4,16

  1. Division of Neuroscience, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
  2. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
  3. Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
  4. Department of Medicine, Children's Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
  5. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
  6. Department of Pathology and Neurosurgical Service, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
  7. Whitehead Institute/MIT Center for Genome Research, AI Lab, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
  8. McGovern Institute, Center for Biological and Computational Learning, AI Lab, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
  9. Division of Pediatric Oncology, Baylor College of Medicine, Houston, Texas 77030, USA
  10. Beth Israel Medical Center, New York 10128, USA
  11. Department of Pathology, New York University School of Medicine, New York 10016, USA
  12. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA
  13. Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA
  14. Division of Human Genetics, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
  15. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
  16. IBM Watson Research Center, Yorktown Heights, New York 10598, USA

Correspondence to: Scott L. Pomeroy1Todd R. Golub2,4,16 Correspondence and requests for materials should be addressed to S.L.P. (e-mail: Email: scott.pomeroy@tch.harvard.edu) or T.R.G. (e-mail: Email: golub@genome.wi.mit.edu).

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Embryonal tumours of the central nervous system (CNS) represent a heterogeneous group of tumours about which little is known biologically, and whose diagnosis, on the basis of morphologic appearance alone, is controversial. Medulloblastomas, for example, are the most common malignant brain tumour of childhood, but their pathogenesis is unknown, their relationship to other embryonal CNS tumours is debated1, 2, and patients' response to therapy is difficult to predict3. We approached these problems by developing a classification system based on DNA microarray gene expression data derived from 99 patient samples. Here we demonstrate that medulloblastomas are molecularly distinct from other brain tumours including primitive neuroectodermal tumours (PNETs), atypical teratoid/rhabdoid tumours (AT/RTs) and malignant gliomas. Previously unrecognized evidence supporting the derivation of medulloblastomas from cerebellar granule cells through activation of the Sonic Hedgehog (SHH) pathway was also revealed. We show further that the clinical outcome of children with medulloblastomas is highly predictable on the basis of the gene expression profiles of their tumours at diagnosis.