Non-myogenic tumors display altered expression of dystrophin (DMD) and a high frequency of genetic alterations

Abstract

DMD gene mutations have been associated with the development of Dystrophinopathies. Interestingly, it has been recently reported that DMD is involved in the development and progression of myogenic tumors, assigning DMD a tumor suppressor activity in these types of cancer. However, there are only few reports that analyze DMD in non-myogenic tumors. Our study was designed to examine DMD expression and genetic alterations in non-myogenic tumors using public repositories. We also evaluated the overall survival of patients with and without DMD mutations. We studied 59 gene expression microarrays (GEO database) and RNAseq (cBioPortal) datasets that included 9817 human samples. We found reduced DMD expression in 15/27 (56%) pairwise comparisons performed (Fold-Change (FC) ≤ 0.70; p-value range = 0.04-1.5×10−20). The analysis of RNAseq studies revealed a median frequency of DMD genetic alterations of 3.4%, higher or similar to other well-known tumor suppressor genes. In addition, we observed significant poorer overall survival for patients with DMD mutations. The analyses of paired tumor/normal tissues showed that the majority of tumor specimens had lower DMD expression compared to their normal adjacent counterpart. Interestingly, statistical significant over-expression of DMD was found in 6/27 studies (FC ≥ 1.4; p-value range = 0.03-3.4×10−15). These results support that DMD expression and genetic alterations are frequent and relevant in non-myogenic tumors. The study and validation of DMD as a new player in tumor development and as a new prognostic factor for tumor progression and survival are warranted.

Comparative two‐dimensional polyacrylamide gel electrophoresis (2D‐PAGE) of human milk to identify dysregulated proteins in breast cancer

“…In this complex, dystroglycan binds to dystrophin in cytoskeleton and acts as a bond between cytoskeleton and extracellular matrix. In a study done on 16 types of tumor tissues, all non‐myogenic (27 paired comparison groups, including 1765 human cases) the gene expression of DMD was downregulated in 15 out of 27 (56%) of paired groups . Except for downregulation of dystrophin, dystroglycan also has showed downregulation in cancer previously.…”

The Duchenne muscular dystrophy gene and cancer

“…The tumours expressed lower levels of lamin B1 (a Dp71-binding partner), matrix metalloproteinase 2 (MMP-2) and B cell lymphoma 2 (Bcl-2) [24], which the authors linked to the reduced malignancy in this model. Subsequently, Luce et al reported significantly reduced DMD expression in lung adenocarcinoma and non-small cell lung carcinoma tissues vs. normal lung tissues using data obtained from the GEO repository with a probe set that detects all DMD transcripts [43]. Given the findings of Tan et al and the evidence from other tumours discussed in this review, it is possible that the reduced expression observed by Luce et al relates to reduced Dp427 expression, but further study is needed to confirm this hypothesis.…”

Somatic Genetic Aberrations in Benign Breast Disease and the Risk of Subsequent Breast Cancer

“…A recently published pan-cancer molecular study of gynecologic and breast cancers revealed that one of the genes displaying significant copy number loss when comparing pan-gynecologic to non-gynecologic is DMD 56 . Another study using data from cBioPortal, which collates next generation sequencing data from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), discovered a median mutation frequency of almost 4% in DMD in sporadic breast cancers 54 . This frequency is identical to that of more well know tumor suppressor genes in breast cancer, PTEN and ARID1A.…”