Subjects

Abstract

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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J. Neuropathol. Exp. Neurol. 42, 1–15 (1983).

  2. 2.

    , & Neonatal cerebellar medulloblastoma originating from the fetal external granular layer. J. Neuropath. Exp. Neurol. 29, 583–600 (1970).

  3. 3.

    et al. Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: a children's cancer group study. J. Clin. Oncol. 17, 2127–2136 (1999).

  4. 4.

    , & Multivariate Analysis (Academic, London, 1979).

  5. 5.

    , , & Cluster analysis and display of genome-wide expression patterns. Proc. Natl Acad. Sci. USA 95, 14863–14868 (1998).

  6. 6.

    et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 286, 531–537 (1999).

  7. 7.

    et al. A novel zinc finger protein, Zic, is involved in neurogenesis, especially in the cell lineage of cerebellar granule cells. J. Neurochem. 63, 1880–1890 (1994).

  8. 8.

    et al. Predominant expression of human Zic in cerebellar granule cell lineage and medulloblastoma. Cancer Res. 56, 377–383 (1996).

  9. 9.

    , & Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity. J. Neurosurg. 85, 56–65 (1996).

  10. 10.

    et al. Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res. 59, 74–79 (1999).

  11. 11.

    et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394, 203–206 (1998).

  12. 12.

    et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85, 841–851 (1996).

  13. 13.

    et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272, 1668–1671 (1996).

  14. 14.

    et al. Medulloblastomas of the desmoplastic variant carry mutations of the human homologue of Drosophila patched. Cancer Res. 57, 2085–2088 (1997).

  15. 15.

    et al. Sporadic medulloblastomas contain PTCH mutations. Cancer Res. 57, 842–845 (1997).

  16. 16.

    et al. Mutations of the PATCHED gene in several types of sporadic extracutaneous tumors. Cancer Res. 57, 2369–2372 (1997).

  17. 17.

    & Control of neuronal precursor proliferation in the cerebellum by Sonic Hedgehog. Neuron 22, 103–114 (1999).

  18. 18.

    , & The normal patched allele is expressed in medulloblastomas from mice with heterozygous germ-line mutation of patched. Cancer Res. 60, 2239–2246 (2000).

  19. 19.

    et al. in World Health Organization Histological Classification of Tumours of the Nervous System (eds Kleihues, P. & Cavenee, W. K.) 129–137 (International Agency for Research on Cancer, Lyon, 2000).

  20. 20.

    , & Sonic hedgehog signaling by the patched-smoothened receptor complex. Curr. Biol. 28, 76–84 (1999).

  21. 21.

    et al. Patched target IGF2 is indispensable for the formation of medulloblastoma and rhabdomyosarcoma. J. Biol. Chem. 275, 28341–28344 (2000).

  22. 22.

    , , , & Expression of the neurotrophin receptor TRKC is linked to a favorable outcome in medulloblastoma. Proc. Natl Acad. Sci. USA 91, 12867–12871 (1994).

  23. 23.

    et al. Activation of neurotrophin-3 receptor TRKC induces apoptosis in medulloblastomas. Cancer Res. 59, 711–719 (1999).

  24. 24.

    et al. Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease. Nature Genet. 29, 143–152 (2001).

  25. 25.

    et al. Interpreting patterns of gene expression with self-organizing maps: Methods and application to hematopoietic differentiation. Proc. Natl Acad. Sci. USA 96, 2907–2912 (1999).

  26. 26.

    (ed). Nearest Neighbor (NN) Norms: NN Pattern Classification Techniques (IEEE Computer Society Press, Los Alamitos, California, 1991).

  27. 27.

    et al. in Proc. 4th Annu. Int. Conf. Computational Mol. Biol. 263–272 (ACM Press, New York, 2000).

  28. 28.

    et al. Support vector machine classification of microarray data. CBCL paper 182/AI memo 1676 (Massachusetts Institute of Technology, Cambridge, Massachusetts, 1999); also at .

  29. 29.

    et al. Knowledge-based analysis of microarray gene expression data by using support vector machines. Proc. Natl Acad. Sci. USA 97, 262–267 (2000).

  30. 30.

    et al. in Proc. 8th Int. Conf. Intel. Syst. Mol. Biol. (eds Bourne, P. et al.) 75–85 (AAAI Press, Menlo Park, CA, 2000.

Download references

Acknowledgements

We thank members of the Whitehead/MIT Center for Genome Research, Program in Cancer Genomics, and J. Volpe for discussions and comments on the manuscript. This work was supported in part by Millennium Pharmaceuticals, Affymetrix and Bristol-Myers Squibb (E.S.L.); NIH grants (S.L.P. and T.C.); NIH-supported Mental Retardation Research Center (S.L.P.) and Cancer Center Support CORE (T.C.); the American Lebanese Syrian Associated Charities (ALSAC); and the Kyle Mullarkey Medulloblastoma Research Fund. We acknowledge the Cooperative Human Tissue Network and the Children's Oncology Group for contributing tumour samples.

Author information

Affiliations

  1. *Division of Neuroscience, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Scott L. Pomeroy
    • , Lisa M. Sturla
    •  & John Y. H. Kim
  2. ‡Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Margaret E. McLaughlin
  3. Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Liliana C. Goumnerova
    •  & Peter M. Black
  4. Department of Medicine, Children's Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Todd R. Golub
  5. §Department of Pediatric Oncology, Dana-Farber Cancer Institute, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • John Y. H. Kim
    •  & Todd R. Golub
  6. ¶¶Department of Pathology and Neurosurgical Service, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • David N. Louis
  7. †Whitehead Institute/MIT Center for Genome Research, AI Lab, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Pablo Tamayo
    • , Michelle Gaasenbeek
    • , Michael Angelo
    • , Jill P. Mesirov
    • , Eric S. Lander
    •  & Todd R. Golub
  8. §§McGovern Institute, Center for Biological and Computational Learning, AI Lab, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Tomaso Poggio
    • , Shayan Mukherjee
    •  & Ryan Rifkin
  9. ¶Division of Pediatric Oncology, Baylor College of Medicine, Houston, Texas 77030, USA

    • Ching Lau
  10. #Beth Israel Medical Center, New York 10128, USA

    • Jeffrey C. Allen
  11. Department of Pathology, New York University School of Medicine, New York 10016, USA

    • David Zagzag
  12. **Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA

    • James M. Olson
  13. ††Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA

    • Tom Curran
    •  & Cynthia Wetmore
  14. ‡‡Division of Human Genetics, The Children's Hospital of Philadelphia, Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA

    • Jaclyn A. Biegel
  15. ##Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Eric S. Lander
  16. IBM Watson Research Center, Yorktown Heights, New York 10598, USA

    • Andrea Califano
    •  & Gustavo Stolovitzky

Authors

  1. Search for Scott L. Pomeroy in:

  2. Search for Pablo Tamayo in:

  3. Search for Michelle Gaasenbeek in:

  4. Search for Lisa M. Sturla in:

  5. Search for Michael Angelo in:

  6. Search for Margaret E. McLaughlin in:

  7. Search for John Y. H. Kim in:

  8. Search for Liliana C. Goumnerova in:

  9. Search for Peter M. Black in:

  10. Search for Ching Lau in:

  11. Search for Jeffrey C. Allen in:

  12. Search for David Zagzag in:

  13. Search for James M. Olson in:

  14. Search for Tom Curran in:

  15. Search for Cynthia Wetmore in:

  16. Search for Jaclyn A. Biegel in:

  17. Search for Tomaso Poggio in:

  18. Search for Shayan Mukherjee in:

  19. Search for Ryan Rifkin in:

  20. Search for Andrea Califano in:

  21. Search for Gustavo Stolovitzky in:

  22. Search for David N. Louis in:

  23. Search for Jill P. Mesirov in:

  24. Search for Eric S. Lander in:

  25. Search for Todd R. Golub in:

Competing interests

We received research funding from Affymetrix (manufacturer of the microarrays used in this study) but do not have a financial (ownership) interest in the company.

Corresponding authors

Correspondence to Scott L. Pomeroy or Todd R. Golub.

Supplementary information

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/415436a

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.