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Nat Genet. 2014 Jun;46(6):601-6. doi: 10.1038/ng.2974. Epub 2014 May 4.

Dystrophin is a tumor suppressor in human cancers with myogenic programs.

Author information

1
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
2
Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Children's Hospital, Boston, Massachusetts, USA.
3
1] Genetic Diagnostic Laboratory, Department of Laboratory Medicine, Children's Hospital, Boston, Massachusetts, USA. [2] Department of Laboratory Medicine, Shanghai Children's Medical Center, Jiaotong University, Shanghai, China.
4
1] Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. [2] Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan.
5
Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
6
Molecular Diagnostics Laboratory, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
7
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
8
Department of Pathology, Stanford University Medical Center, Stanford, California, USA.
9
Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
10
Ludwig Center at Harvard, Harvard Medical School and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
11
1] Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA. [2] Enteric Neuroscience Program, Mayo Clinic, Rochester, Minnesota, USA. [3] Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA.

Abstract

Many common human mesenchymal tumors, including gastrointestinal stromal tumor (GIST), rhabdomyosarcoma (RMS) and leiomyosarcoma (LMS), feature myogenic differentiation. 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.

PMID:
24793134
PMCID:
PMC4225780
DOI:
10.1038/ng.2974
[Indexed for MEDLINE]
Free PMC Article

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