Differential expression of DMD transcripts as a novel prognostic biomarker in histologically diverse mesotheliomas

Our plain-English summary of Differential expression of DMD transcripts as a novel prognostic biomarker in histologically diverse mesotheliomas, by N. Alnassar, J.M.J. Derry, G.L. Banna, et al (Translational Lung Cancer Research, 2024).

The study

• Authors: N. Alnassar, J.M.J. Derry, G.L. Banna, D.C. Gorecki
• Journal: Translational Lung Cancer Research
• Published: 2024;13(4):733-748
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: The identification of prognostic biomarkers is crucial for guiding treatment strategies in mesothelioma patients. The Duchenne muscular dystrophy (DMD) gene and its specific transcripts have been associated with patient survival in various tumours. In this study, we aimed to investigate the prognostic potential of DMD gene expression and its transcripts in mesothelioma patients.

Methods: We analysed The Cancer Genome Atlas (TCGA) mesothelioma RNAseq, mutation, and clinical data to assess the association between DMD gene expression and its transcripts (Dp427, Dp71 splice variants) and mesothelioma survival. We also evaluated the specific Dp71 transcript as a unique prognostic biomarker across mesothelioma subtypes. Additionally, we performed differential gene expression analysis between high and low DMD gene/transcript expression groups.

Results: The analysis included 57 epithelioid, 23 biphasic, two sarcomatoid, and five not otherwise specified (NOS) histological subtypes of mesothelioma samples. Univariate analysis revealed that high expression of the DMD gene and its Dp71 transcript was significantly associated with shorter survival in mesothelioma patients (P=0.003 and P<0.001, respectively). In a multivariate analysis, the association between Dp71 expression and survival remained significant [hazard ratio (HR) 2.29, 95% confidence interval (CI): 1.24-4.23, P=0.008] across all mesothelioma patients, and also among patients with mesotheliomas without deep CDKN2A deletions (HR 3.58, 95% CI: 1.31-9.80, P=0.01). Pathway analysis revealed enrichment of cell cycle (P=3.01×10-4) and homologous recombination (P=0.01) pathways in differentially expressed genes (DEGs) between high and low Dp71 groups. Furthermore, there were correlations between Dp71 transcript expression and tumour microenvironment (TME) cells, including a weak positive correlation with macrophages (R=0.32, P=0.002) specifically M2 macrophages (R=0.34, P=0.001).

Conclusions: Our findings indicate that the differential expression of specific DMD transcripts is associated with poor survival in mesothelioma patients. The specific Dp71 transcript can serve as a potential biomarker for predicting patient survival in diverse histological subtypes of mesothelioma. Further studies are needed to understand the role of specific dystrophin transcripts in cancer and TME cells, and their implications in the pathogenesis and progression of mesothelioma. Identifying patients at risk of poor survival based on DMD transcript expression can guide treatment strategies in mesothelioma, informing decisions regarding treatment intensity, follow-up schedules, eligibility for clinical trials, and ultimately, end-of-life care planning.

2024 Translational Lung Cancer Research. All rights reserved.

In plain English

This study did not examine asbestos exposure. The authors reanalysed publicly available data from The Cancer Genome Atlas mesothelioma cohort: 87 tumour samples (57 epithelioid, 23 biphasic, two sarcomatoid, five not otherwise specified) from 71 men and 16 women. They asked whether expression (activity) levels of the DMD gene, which makes the protein dystrophin, and of its transcript forms such as Dp71 were linked to survival. Patients were split into high and low groups using software that picks the cut-off giving the smallest P value. Median survival was 14.99 months in the high total-DMD group versus 27.16 months in the low group. It was 8.351 versus 19.99 months for high versus low Dp71. Two other forms, Dp71a and Dp427m, showed no association with survival. After adjusting for histology and CDKN2A and NF2 deletion status, high Dp71 remained linked to shorter survival (hazard ratio 2.291, 95% confidence interval 1.24 to 4.230). The authors concluded that Dp71 expression is an independent prognostic marker for mesothelioma. They noted that the cohort was relatively small and that the findings need validation in a larger independent cohort.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective analysis of existing public genomic and clinical data (The Cancer Genome Atlas mesothelioma cohort), including survival analysis with Kaplan-Meier curves, log-rank tests and multivariate Cox regression
• Who was studied: 87 mesothelioma tumour samples from the TCGA MESO cohort: 57 epithelioid, 23 biphasic, two sarcomatoid and five not otherwise specified. There were 71 male and 16 female patients, aged 28 to 81 at diagnosis. One sarcomatoid sample was excluded from survival analyses because it had no survival data.
• Exposure: No asbestos or fiber exposure was studied. The factor examined was tumour expression of the DMD (dystrophin) gene and its transcripts: Dp427m and the Dp71 splice variants Dp71, Dp71a, Dp71b and Dp71ab. Expression was classed as high or low using cut-offs chosen by a minimal P value approach.
• Main results:
  • Total DMD gene expression: median survival was 14.99 months in the high group compared with 27.16 months in the low group (log-rank P=0.003).
  • Median survival was 8.351, 14.99 and 16.18 months for the high Dp71, Dp71b and Dp71ab groups. The matching low groups had 19.99, 24.07 and 19.99 months.
  • No association with survival was found for Dp71a or Dp427m expression.
  • In a multivariate analysis across all patients, adjusting for histology and CDKN2A and NF2 deletion status, high versus low Dp71 remained significantly associated with survival (HR 2.291, 95% CI 1.24 to 4.230, P=0.008). CDKN2A deep deletion status also remained significant (HR 2.966, 95% CI 1.722 to 5.110).
  • Among patients without deep CDKN2A deletions, high Dp71 remained significantly associated with survival in a multivariate analysis (HR 3.582, 95% CI 1.309 to 9.802, P=0.01). Median overall survival was 13.61 months in the high Dp71 group versus 27.16 months in the low Dp71 group.
  • Patients with non-epithelioid mesothelioma had worse overall survival than those with the epithelioid subtype (HR 1.771). No effect was found for gender, age at diagnosis or tumour stage in this cohort.
  • Genes that differed between the high and low Dp71 groups were enriched in cell cycle and homologous recombination pathways.
  • Dp71 expression showed a weak positive correlation with the algorithm-predicted percentage of macrophages (R=0.32, P=0.002) and of M2 macrophages (R=0.34, P=0.001) in the tumour microenvironment.
  • DMD gene deletions or mutations were not overrepresented in either the high or the low DMD expression group (P greater than 0.99).
• The authors' conclusion: The authors concluded that expression of the Dp71 transcript of the DMD gene is an independent prognostic marker for mesothelioma. They suggested that measuring it could potentially be developed into a prognostic and predictive biomarker test.
• Limitations the authors state:
  • The patient cohort from the TCGA MESO dataset was relatively small, and the findings need validation in a larger independent cohort.
  • There were no normal control tissue data, so the authors could not tell whether Dp71 expression differs between mesothelioma and normal pleura.
  • Transcript-level expression estimates may not be fully accurate because of mapping ambiguities.
  • The data could not establish whether Dp71 plays a causal role or is only a passive marker.

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Mesothelioma, Epithelioid, Biphasic Mesothelioma, Sarcomatoid, Histological Subtype, Multivariate Analysis, Hazard Ratio.

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