Downregulation of Dystrophin Expression Occurs across Diverse Tumors, Correlates with the Age of Onset, Staging and Reduced Survival of Patients

Simple Summary Mutations of the DMD gene, encoding dystrophins, cause Duchenne muscular dystrophy (DMD). We found that while DMD transcription occurs throughout a spectrum of normal tissues, it is frequently downregulated across various malignancies. The molecular signature associated with this downregulation matches transcriptomic changes found in Duchenne muscles, even though most of these malignancies originate from tissues never previously associated with dystrophin expression or function. Importantly, we found that reduced DMD expression across different tumors was associated with reduced patients' survival and higher tumor stage. These findings call for re-evaluation of the current view that dystrophin expression found across numerous tissues is the result of an "illegitimate transcription" and demonstrate that the significance of this gene goes beyond its known involvement in Duchenne muscular dystrophy. Moreover, these data unite and explain the growing evidence that the DMD gene has a role in tumors. Altered dystrophin expression was found in some tumors and recent studies identified a developmental onset of Duchenne muscular dystrophy (DMD). Given that embryogenesis and carcinogenesis share many mechanisms, we analyzed a broad spectrum of tumors to establish whether dystrophin alteration evokes related outcomes. Transcriptomic, proteomic, and mutation datasets from fifty tumor tissues and matching controls (10,894 samples) and 140 corresponding tumor cell lines were analyzed. Interestingly, dystrophin transcripts and protein expression were found widespread across healthy tissues and at housekeeping gene levels. In 80% of tumors, DMD expression was reduced due to transcriptional downregulation and not somatic mutations. The full-length transcript encoding Dp427 was decreased in 68% of tumors, while Dp71 variants showed variability of expression. Notably, low expression of dystrophins was associated with a more advanced stage, older age of onset, and reduced survival across different tumors. Hierarchical clustering analysis of DMD transcripts distinguished malignant from control tissues. Transcriptomes of primary tumors and tumor cell lines with low DMD expression showed enrichment of specific pathways in the differentially expressed genes. Pathways consistently identified: ECM-receptor interaction, calcium signaling, and PI3K-Akt are also altered in DMD muscle. Therefore, the importance of this largest known gene extends beyond its roles identified in DMD, and certainly into oncology.