The Role of the DMD Gene in Tumour Biology and its Association with Patient Survival across Diverse Malignancies

Student thesis: Doctoral Thesis

Abstract

Abstract
Alterations in the Duchenne muscular dystrophy (DMD) gene expression have been reported in diverse malignancies. This largest known human gene encodes multiple dystrophin isoforms through unique promotor usage and alternative splicing. The full-length Dp427 and the shorter ubiquitous Dp71 isoforms play distinct roles in tumours. Dp71 can have oncogenic or tumour suppressive roles, potentially due to the expression of two groups of Dp71 splice variants with structurally and functionally distinct C-termini. Initially, a comprehensive bioinformatics analysis of the expression of the DMD gene and its Dp427 and Dp71 transcripts in primary tumours and control tissues was performed. The association of DMD expression with patient survival and transcriptomic alterations in tumour cells were evaluated. The role of the Dp71f variant, characterised by an alternative C-terminus, was also examined by ablating its expression in A673 cells. The findings revealed widespread DMD expression in healthy tissues, comparable to housekeeping genes, with dystrophin acting as a housekeeping protein. In tumours, DMD expression is reduced compared to control tissues due to regulatory mechanisms. This downregulation is associated with reduced survival and a molecular signature that is concordant with alterations found in muscles of DMD patients, even though these tumours originate from tissues never previously associated with any dystrophin functions. The expression of Dp71 splice variants showed variability of expression in tumours. Therefore, a targeted analysis of DMD transcripts expression in specific tumour types was performed. It was found that Dp71 is an independent prognostic marker in mesothelioma. In histologically-diverse sarcomas, expression of the DMD gene or its transcripts is associated with survival in multivariate analyses. In mesotheliomas and sarcomas, expression of DMD transcripts correlated with tumour microenvironment cells. Finally, this project identified a role for Dp71f in influencing calcium homeostasis, proliferation, adhesion, survival and response to chemotherapy in tumour cells, rendering Dp71f an intriguing target for future research. These findings highlight the role of DMD gene/transcripts in tumours and their effects on tumour biology and patient survival. Quantification of DMD transcripts in specific tumours could be developed into a prognostic biomarker test to improve risk stratification and guide treatment decisions. Furthermore, DMD transcripts could be investigated as therapeutic targets in cases where their high expression is associated with poor survival. In summary, the role of the DMD gene extend beyond its traditionally recognised role in muscular dystrophy.

Date of Award14 May 2024
Original languageEnglish
Awarding Institution
  • University of Portsmouth
SupervisorDarek Gorecki (Supervisor) & Matthew Parker (Supervisor)

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