Downregulation of dystrophin expression occurs across diverse tumors, correlates with the age of onset, staging and reduced survival of patients

Abstract

AbstractMutations of theDMDgene, encoding dystrophins, cause Duchenne muscular dystrophy (DMD). Some tumors also display altered dystrophin expression and recent studies identified a developmental onset of DMD. Given that embryogenesis and carcinogenesis share many mechanisms, we analyzed a broad spectrum of tumors to establish whether dystrophin loss 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,DMDexpression was widespread across healthy tissues at levels comparable to housekeeping genes. In 80% of tumors,DMDexpression 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. Hierarchical clustering analysis ofDMDtranscripts distinguished malignant from control tissues. Transcriptomes of primary tumors and tumor cell lines with lowDMDexpression 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. Notably, lowDMDexpression was associated with a more advanced stage, older age of onset, and reduced survival across different tumors. Thus,DMDtranscription occurs throughout a spectrum of normal tissues. The molecular signature associated with its frequent downregulation in malignancies is concordant with changes found in Duchenne muscles, even though these malignancies originate from tissues never previously associated with dystrophin expression or function. Therefore, the importance of this largest known gene extends beyond its roles identified in DMD, certainly into oncology.