Dystrophin (DMD) deletions are frequent in GIST, RMS, and LMS and confer metastatic properties.

  • Major finding: Dystrophin (DMD) deletions are frequent in GIST, RMS, and LMS and confer metastatic properties.

  • Concept: Intragenic DMD deletions lead to inactivation of large dystrophin isoform but not an essential isoform.

  • Impact: Therapies developed for muscular dystrophies should be evaluated in myogenic sarcomas.

Gastrointestinal stromal tumor (GIST), rhabdomyosarcoma (RMS), and leiomyosarcoma (LMS) are soft tissue sarcomas that frequently express myogenic differentiation markers. Wang and colleagues sought to identify shared factors contributing to the development of myogenic cancers using single-nucleotide polymorphism arrays and found that 63% of high-grade myogenic cancers harbored intragenic deletions in the longest human gene, dystrophin (DMD), which encodes a sarcolemmal protein that structurally links the actin cytoskeleton with the extracellular matrix. DMD deletions were not identified in nonmyogenic sarcomas and were rarely observed in nonsarcoma cell lines. Both normal myogenic tissues and benign precursors of myogenic cancers expressed high levels of several dystrophin isoforms. However, metastatic myogenic tumors specifically exhibited deletions of DMD exons 1 to 62, which resulted in loss of the large 427-kDa dystrophin isoform in 96% of metastatic GIST, 100% of metastatic embryonal RMS, and 62% of metastatic LMS samples assayed. Despite the loss of the 427-kDa isoform, metastatic tumors retained expression of a 71-kDa dystrophin isoform encoded by exons 63 to 79. Knockdown of 71-kDa dystrophin impaired growth of RMS cells, indicating it was essential for myogenic tumors. Reexpression of a DMD construct lacking exons 17 through 48, which encodes a functional 240-kDa dystrophin isoform, suppressed migration, invasiveness, invadopodia formation, and anchorage-independent growth of GIST, RMS, and LMS cells, suggesting that dystrophin inactivation promotes metastatic behavior. In addition to providing evidence that dystrophin acts as a tumor suppressor in myogenic cancers, these data suggest that muscular dystrophy therapies that aim to correct dystrophin defects should also be evaluated in myogenic cancers.

Wang Y, Marino-Enriquez A, Bennett RR, Zhu M, Shen Y, Eilers G, et al. Dystrophin is a tumor suppressor in human cancers with myogenic programs. Nat Genet 2014 May 4 [Epub ahead of print].