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Abstract

The sonic hedgehog (SHH) signaling pathway directs the embryonic development of diverse organisms and is disrupted in a variety of malignancies. Pathway activation is triggered by binding of hedgehog proteins to the multipass Patched-1 (PTCH) receptor, which in the absence of hedgehog suppresses the activity of the seven-pass membrane protein Smoothened (SMOH). De-repression of SMOH culminates in the activation of one or more of the GLI transcription factors that regulate the transcription of downstream targets. Individuals with germline mutations of the SHH receptor gene PTCH are at high risk of developmental anomalies and of basal-cell carcinomas, medulloblastomas and other cancers (a pattern consistent with nevoid basal-cell carcinoma syndrome, NBCCS). In keeping with the role of PTCH as a tumor-suppressor gene, somatic mutations of this gene occur in sporadic basal-cell carcinomas and medulloblastomas. We report here that a subset of children with medulloblastoma carry germline and somatic mutations in SUFU (encoding the human suppressor of fused) of the SHH pathway, accompanied by loss of heterozygosity of the wildtype allele. Several of these mutations encode truncated proteins that are unable to export the GLI transcription factor from nucleus to cytoplasm, resulting in the activation of SHH signaling. SUFU is a newly identified tumor-suppressor gene that predisposes individuals to medulloblastoma by modulating the SHH signaling pathway through a newly identified mechanism.

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Acknowledgements

We thank the individuals and families who agreed to take part in these studies, and members of the McGlade laboratory for helpful discussions. This work was supported by the National Cancer Institute of Canada (NCIC) and the Michael Young Melanoma Fund (D.H.), a Terry Fox New Frontiers Award from the NCIC (C.C.H. and J.T.R.), the Canadian Institutes of Health Research (J.T.R. and C.C.H.) and Brainchild (J.T.R.). M.D.T. and T.G.M. were supported by Terry Fox fellowships from the NCIC with funds from the Terry Fox run. M.D.T. was subsequently supported by a fellowship from the Neurosurgery Research and Education Foundation.

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Affiliations

  1. Division of Neurosurgery, The Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Canada.

    • Michael D. Taylor
    • , Todd G. Mainprize
    •  & James T. Rutka
  2. Department of Laboratory Medicine and Pathobiology, Hospital for Sick Children, Toronto, Canada.

    • Michael D. Taylor
    •  & James T. Rutka
  3. Division of Clinical Science, University of Toronto, Canada.

    • Ling Liu
    • , Luzhang Gao
    • , Anja Lowrance
    • , Aihau Hao
    • , Stephen W. Scherer
    •  & David Hogg
  4. Department of Medical Biophysics, University of Toronto, Canada.

    • Ron Agatep
    •  & David Hogg
  5. Department of Medicine, University of Toronto, Canada.

    • Stephen W. Scherer
    •  & David Hogg
  6. Department of Molecular and Medical Genetics, University of Toronto, Canada.

    • Chi-chung Hui
    •  & Xiaoyun Zhang
  7. Department of Neurosurgery, Mayo Clinic, Rochester, Minnesota, USA.

    • Corey Raffel
    •  & Sharon Chiappa
  8. Genetic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

    • Alisa M. Goldstein
    •  & Theodora Stavrou
  9. Department of Hematology–Oncology, Children's National Medical Center, Washington, District of Columbia, USA.

    • Theodora Stavrou
  10. Department of Pathology, University of Warsaw, Poland.

    • Wieslaw T. Dura
  11. Ritchie Research Laboratories, University of Queensland, St. Lucia, Australia.

    • Brandon Wainwright
  12. Ontario Cancer Institute, Princess Margaret Hospital, Departments of Laboratory Medicine and Pathobiology and Medical Biophysics, University of Toronto, Canada.

    • Jeremy A. Squire

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The authors declare no competing financial interests.

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Correspondence to James T. Rutka or David Hogg.

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DOI

https://doi.org/10.1038/ng916