Many common human mesenchymal tumors, including gastrointestinal stromal tumor (GIST), rhabdomyosarcoma (RMS) and leiomyosarcoma (LMS), feature myogenic differentiation1,2,3. Here we report that intragenic deletion of the dystrophin-encoding and muscular dystrophy–associated DMD gene is a frequent mechanism by which myogenic tumors progress to high-grade, lethal sarcomas. Dystrophin is expressed in the non-neoplastic and benign counterparts of GIST, RMS and LMS tumors, and DMD deletions inactivate larger dystrophin isoforms, including 427-kDa dystrophin, while preserving the expression of an essential 71-kDa isoform. Dystrophin inhibits myogenic sarcoma cell migration, invasion, anchorage independence and invadopodia formation, and dystrophin inactivation was found in 96%, 100% and 62% of metastatic GIST, embryonal RMS and LMS samples, respectively. These findings validate dystrophin as a tumor suppressor and likely anti-metastatic factor, suggesting that therapies in development for muscular dystrophies may also have relevance in the treatment of cancer.

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We thank J. Tremblay (Quebec University Hospital) for the pCR3.1-miniDMD construct; T. Taguchi (Kochi Medical School) for the GIST-T1 cell line; Y. Hayashi, M. Bardsley and H. Qiu for their expert technical assistance; and S. Bauer (West German Cancer Center) for useful discussions and for funding support of J.H. This work was supported by grants from the US National Institutes of Health, including 1P50CA127003-07 (J.A.F. and G.D.D.), 1P50CA168512-01 (J.A.F., G.D.D. and A.M.-E.) and 5R01DK058185-12 (T.O.), and by the Virginia and Daniel K. Ludwig Trust for Cancer Research (J.A.F. and G.D.D.), the GIST Cancer Research Fund (J.A.F.), the Life Raft Group (J.A.F., T.O. and M.v.d.R.), the Cesarini Pan-Mass Challenge for GIST (J.A.F. and G.D.D.), Paul's Posse of the Pan-Mass Challenge (J.A.F. and G.D.D.), the Bernard F. and Alva B. Gimbel Foundation (L.M.K.), the Sarcoma Alliance for Research Through Collaboration (A.M.-E.) and the Erica Kaitz LMS Research NOW Fund (J.A.F., A.M.-E. and G.D.D.).

Author information


  1. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Yuexiang Wang
    • , Adrian Marino-Enriquez
    • , Meijun Zhu
    • , Grant Eilers
    • , Jen-Chieh Lee
    • , Joern Henze
    • , Benjamin S Fletcher
    • , Christopher D M Fletcher
    •  & Jonathan A Fletcher
  2. Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Children's Hospital, Boston, Massachusetts, USA.

    • Richard R Bennett
    •  & Louis M Kunkel
  3. Genetic Diagnostic Laboratory, Department of Laboratory Medicine, Children's Hospital, Boston, Massachusetts, USA.

    • Yiping Shen
  4. Department of Laboratory Medicine, Shanghai Children's Medical Center, Jiaotong University, Shanghai, China.

    • Yiping Shen
  5. Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.

    • Jen-Chieh Lee
  6. Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Zhizhan Gu
  7. Molecular Diagnostics Laboratory, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • Edward A Fox
  8. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.

    • Cristina R Antonescu
  9. Department of Pathology, Stanford University Medical Center, Stanford, California, USA.

    • Xiangqian Guo
    •  & Matt van de Rijn
  10. Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Chandrajit P Raut
  11. Ludwig Center at Harvard, Harvard Medical School and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.

    • George D Demetri
  12. Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA.

    • Tamas Ordog
  13. Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota, USA.

    • Tamas Ordog
  14. Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA.

    • Tamas Ordog


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J.A.F. supervised the project. Y.W. and J.A.F. generated the original hypothesis and designed the study. Y.W., A.M.-E., R.R.B., M.Z., Y.S., G.E., J.-C.L., J.H., B.S.F., Z.G., Y.S., X.G. and T.O. performed experiments. A.M.-E., C.R.A., C.D.M.F., C.P.R., M.v.d.R. and J.A.F. provided samples and clinical data. Y.W., A.M.-E., R.R.B., M.Z., Y.S., G.E., J.-C.L., B.S.F., Z.G., E.A.F., X.G., M.v.d.R., T.O., L.M.K. and J.A.F. analyzed data. C.R.A., C.D.M.F., G.D.D., M.v.d.R. and L.M.K. provided scientific advice and helpful comments on the project. Y.W., A.M.-E., G.E. and J.A.F. wrote the manuscript. All authors read and approved the final manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jonathan A Fletcher.

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