Abstract 1572: 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. Although presumptive initiating mutations have been identified in these cancers, the subsequent mechanisms of malignant progression are not known. 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. Genome-wide SNP screens demonstrated DMD intragenic deletions in 23 of 38 myogenic sarcomas (61%) compared to 0 of 58 non-myogenic sarcomas (p < 0.0001). Although DMD is an X-linked gene, somatic DMD deletions affected both sexes equally and DMD deletions in female patients involved the active X chromosome, resulting in functional DMD nullisomy. Dystrophin was expressed strongly in nonneoplastic and benign counterparts for GIST, RMS and LMS, and the DMD deletions in the malignant myogenic sarcomas clustered at the 5′ end of the gene, inactivating larger dystrophin isoforms, including 427kDa dystrophin, while preserving expression of an essential 71kDa isoform (Dp71) which is encoded by the DMD 3′ end. Dystrophin restoration inhibited 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, respectively. The genomic, clinicopathological and functional evidence validate dystrophin as a tumor suppressor and likely anti-metastatic factor, suggesting that therapies in development for muscular dystrophies may also have relevance in treatment of cancer.

Citation Format: Yuexiang Wang, Adrian Marino-Enriquez, Richard Bennett, Meijun Zhu, Grant Eilers, Cristina Antonescu, Christopher Fletche, Chandrajit Raut, Matt van de Rijn, Louis Kunkel, George Demetri, Jonathan Fletcher. Dystrophin Is a tumor suppressor in human cancers with myogenic programs. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1572. doi:10.1158/1538-7445.AM2014-1572