Dystrophin deregulation is associated with tumor progression in KIT/PDGFRA mutant gastrointestinal stromal tumors

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.

Molecular characterization of metastatic exon 11 mutant gastrointestinal stromal tumors (GIST) beyond KIT/PDGFRα genotype evaluated by next generation sequencing (NGS)

“…Moreover PTEN ( p = 0,0062), SMARCB1 ( p = 0,0009) and SMAD4 (not significant) showed a marked gene expression reduction in concordance with CN status. Finally, DMD deletions in patients GIST_131, _174 and _188 were also associated with a significant down-modulation of mRNA expression, as reported elsewhere [ 14 ].…”

“…Wang and colleagues identified DMD deletion as shared factor contributing to the development of myogenic cancers [ 45 ], hypothesizing that DMD inactivation promotes metastatic potential due to its role in regulating migration, invasion, anchorage and invadopodia formation. Recently our group has also reported the recurrence of dystrophin deletion in nine of 35 GIST samples [ 14 ]. These were all KIT/PDGFRα-mutant GISTs, whereas none of the 6 KIT/PDGFRα wild-type GIST samples showed DMD alterations.…”

Integrated Molecular Characterization of Gastrointestinal Stromal Tumors (GIST) Harboring the Rare D842V Mutation in PDGFRA Gene

“…In addition, a focal deletion of dystrophin gene ( DMD ) on chromosome X was found in 42% of tumor samples (corresponding to four patients: P03, P06, P07, and P08). This particular aberration is known to be associated with the metastatic tumors [ 19 , 20 ] even if in our series this evidence is not statistically significant due to the small number of samples. We found also numerous copy number gains (in particular on chromosomes 5, 7, 8, 17, and 19) that, interestingly, occurred mostly in metastatic samples.…”

“…A percentage of 42% of samples (corresponding to four unique patients) showed a focal deletion of dystrophin gene (on chromosome X). Deletions of dystrophin in KIT/PDGFRA mutant GIST have been previously reported and usually are associated with more advanced clinical stages of disease such as metastatic tumors [ 19 , 20 ]. In this study, the deletion of DMD occurred mainly in tumors with a high mitotic index of the primary tumor and in metastatic lesions.…”

Sex-specific gene and pathway modeling of inherited glioma risk

“…34 Deletions in this gene have been found in mesenchymal and stromal tumors, and downregulation of this gene has been associated with progression and metastasis in these tumors. 35,36 ARMCX2 (Xq22.1) is a member of the armadillo family of proteins, several of which have been implicated in tumorigenesis. 37 ARMCX2 has been shown to be differentially expressed in cancer cell lines as compared to normal cell lines, though expression in glioma cell lines does not differ from normal.…”