title: Dystrophin is a tumor suppressor in human cancers with myogenic programs.
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.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yuexiang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Marino-Enriquez
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Bennett
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Meijun
authors.initials: M
authors.lastname: Zhu
authors.affiliation: 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.
authors.forename: Yiping
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Grant
authors.initials: G
authors.lastname: Eilers
authors.affiliation: 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.
authors.forename: Jen-Chieh
authors.initials: JC
authors.lastname: Lee
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Joern
authors.initials: J
authors.lastname: Henze
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Fletcher
authors.affiliation: Division of Rheumatology, Immunology and Allergy, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Zhizhan
authors.initials: Z
authors.lastname: Gu
authors.affiliation: Molecular Diagnostics Laboratory, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fox
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Christopher D M
authors.initials: CD
authors.lastname: Fletcher
authors.affiliation: Department of Pathology, Stanford University Medical Center, Stanford, California, USA.
authors.forename: Xiangqian
authors.initials: X
authors.lastname: Guo
authors.affiliation: Department of Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Chandrajit P
authors.initials: CP
authors.lastname: Raut
authors.affiliation: Ludwig Center at Harvard, Harvard Medical School and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: George D
authors.initials: GD
authors.lastname: Demetri
authors.affiliation: Department of Pathology, Stanford University Medical Center, Stanford, California, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: van de Rijn
authors.affiliation: 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.
authors.forename: Tamas
authors.initials: T
authors.lastname: Ordog
authors.affiliation: Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Children's Hospital, Boston, Massachusetts, USA.
authors.forename: Louis M
authors.initials: LM
authors.lastname: Kunkel
authors.affiliation: Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Fletcher
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D016189:Dystrophin / Q000235:genetics* / Q000502:physiology*; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D056885:Interstitial Cells of Cajal / Q000473:pathology; D007890:Leiomyosarcoma / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D024510:Muscle Development / Q000235:genetics; D018482:Muscle, Skeletal / Q000473:pathology; D009136:Muscular Dystrophies / Q000235:genetics* / Q000473:pathology; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D012208:Rhabdomyosarcoma / Q000235:genetics; D012509:Sarcoma / Q000235:genetics*
chemical_list: C484258:DMD protein, human; D016189:Dystrophin