Exploring Dystrophin Expression and Mutations in the DMD and Dystrophin-Glycoprotein Complex Genes as Prognostic...

Molecular factors influencing prognosis in leiomyosarcomas (LMS) remain poorly understood. Given that LMS arise from smooth muscle and that the dystrophin gene (DMD) has been suggested as a tumor suppressor in this tumor type, this study investigated dystrophin expression and somatic mutations in DMD, and dystrophin-glycoprotein complex (DGC) and dysferlin (DYSF) coding genes as prognostic biomarkers in LMS. Seventy-seven patients with LMS were retrospectively included in the study. Dystrophin expression was evaluated by immunohistochemistry. The presence of DMD point mutations were determined using next-generation sequencing (NGS), and DMD copy-number variants were assessed by multiplex ligation-dependent probe amplification (MLPA) technique. Low dystrophin expression was observed in 66% of tumors and showed a nominal association with tumor grade, with 76% of grade 3, 58% of grade 2, and 33% of grade 1 tumors showing low dystrophin expression (p = 0.046). Dystrophin expression was not associated with overall survival (OS), nor with recurrence-free survival (RFS) in localized cases or progression-free survival (PFS) in metastatic cases. However, dystrophin expression was significantly associated with shorter OS (p = 0.006) and RFS (p = 0.003) in patients with localized grade 2 tumors. Mutations in DMD, DGC-coding genes and DYSF were identified in 59% of tumors, but no significant associations were found with pathological, molecular, or survival data. Loss of dystrophin expression was common in LMS tumors and was associated with high-grade tumors in our cohort. Nonetheless, the role of dystrophin as a prognostic biomarker of survival was only observed in patients with localized grade 2 tumors in this exploratory, hypothesis-generating study, and therefore needs further validation.