Abstract
BackgroundIntragenic deletions of the dystrophin-encoding and muscular dystrophy-associated DMD gene have been recently described in gastrointestinal stromal tumor (GIST), rhabdomyosarcoma (RMS) and leiomyosarcoma (LMS). We evaluated the copy numbers and gene expression levels of DMD in our series of GIST patients who were already studied with wide genome assays, to investigate more fully a correlation between dystrophin status and disease annotations.FindingsOur study highlighted a recurrent intragenic deletion on chromosome X, involving the DMD gene that codes for human dystrophin in GIST patients. Of 29 KIT/PDGFRA mutant GIST samples, 9 (31%) showed deletions of the DMD gene, which were focal and intragenic in 8 cases, and involved loss of an entire chromosome in one case (GIST_188). DMD loss was seen in only 5 patients with metastasis, whereas 18 out of 20 patients with localized disease had wild-type DMD (P = 0.0004, Fisher exact test). None of the 6 KIT/PDGFRA WT GIST showed DMD alterations.ConclusionsOur study confirms the presence of DMD deletions only in KIT/PDGFRA mutant GIST and this event is almost associated with metastatic disease. These findings are, of course, quite preliminary but support development of potential therapeutic strategies that target and restore DMD function in the treatment of metastatic GIST.
Highlights
Intragenic deletions of the dystrophin-encoding and muscular dystrophy-associated Dystrophin-encoding and muscular dystrophy-associated (DMD) gene have been recently described in gastrointestinal stromal tumor (GIST), rhabdomyosarcoma (RMS) and leiomyosarcoma (LMS)
Our study confirms the presence of DMD deletions only in KIT/PDGFRA mutant GIST and this event is almost associated with metastatic disease
Dystrophin inhibits myogenic sarcoma cell migration, invasion, anchorage independence and invadopodia formation; and when deregulated, dystrophin restoration inhibits invasiveness and migration in sarcoma cell lines. These data validate dystrophin as a tumor suppressor and likely anti-metastatic factor. In light of these findings, we evaluated DMD copy number and gene expression levels in our series of GIST patients who had already been studied with wide genome assays, to investigate more fully the correlation between dystrophin status and disease annotations
Summary
Intragenic deletions of the dystrophin-encoding and muscular dystrophy-associated DMD gene have been recently described in gastrointestinal stromal tumor (GIST), rhabdomyosarcoma (RMS) and leiomyosarcoma (LMS). Conclusions: Our study confirms the presence of DMD deletions only in KIT/PDGFRA mutant GIST and this event is almost associated with metastatic disease. In light of these findings, we evaluated DMD copy number and gene expression levels in our series of GIST patients who had already been studied with wide genome assays, to investigate more fully the correlation between dystrophin status and disease annotations.
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