MicroRNA gene expression signatures in long-surviving malignant pleural mesothelioma patients

Our plain-English summary of MicroRNA gene expression signatures in long-surviving malignant pleural mesothelioma patients, by R.C. Lin, M.B. Kirschner, Y.Y. Cheng, et al (Genomics Data, 2016).

The study

• Authors: R.C. Lin, M.B. Kirschner, Y.Y. Cheng, N. van Zandwijk, G. Reid
• Journal: Genomics Data
• Published: 2016;9:44-9
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a tumor originating in the mesothelium, the membrane lining the thoracic cavities, and is induced by exposure to asbestos. Australia suffers one of the world's highest rates of MPM and the incidence is yet to peak. The prognosis for patients with MPM is poor and median survival following diagnosis is 4-18 months. Currently, no or few effective therapies exist for MPM. Trials of targeted agents such as antiangiogenic agents (VEGF, EGFR) or ribonuclease inhibitors (ranpirnase) largely failed to show efficacy in MPM Tsao et al. (2009) [1]. A recent study, however, showed that cisplatin/pemetrexed + bevacizumab (a recombinant humanized monoclonal antibody that inhibit VEGF) treatment has a survival benefit of 2.7 months Zalcman et al. (2016) [2]. It remains to be seen if this targeted therapy will be accepted as a new standard for MPM. Thus the unmet needs of MPM patients remain very pronounced and almost every patient will be confronted with drug resistance and recurrence of disease. We have identified unique gene signatures associated with prolonged survival in mesothelioma patients undergoing radical surgery (EPP, extrapleural pneumonectomy), as well as patients who underwent palliative surgery (pleurectomy/decortication). In addition to data published in Molecular Oncology, 2015;9:715-26 (GSE59180) Kirschner et al. (2015) , we describe here additional data using a system-based approach that support our previous observations. This data provides a resource to further explore microRNA dynamics in MPM.

In plain English

This short data article re-analysed microRNA measurements from the tumours of people with malignant pleural mesothelioma. The same research group had published these data in 2015. The samples were 16 preserved tumour samples from patients in Sydney, Australia, who had undergone extrapleural pneumonectomy, a radical operation. Eight were long survivors (median survival 53.7 months) and 8 were short survivors (median 6.4 months). The authors processed the array data a different way and grouped microRNAs by expression pattern. One cluster of 15 microRNAs was higher in short survivors; for example, hsa-miR-221-3p was 6.45867-fold higher. Another cluster of 15 was lower in short survivors. Gene targets of these microRNAs, predicted from computer databases, were linked to pathways including hippo signaling, focal adhesion and PI3K-Akt signaling. The authors concluded that the new analyses supported their earlier observations, and that the approach could help choose genes for further testing. They noted that computer-predicted targets carry known pitfalls. The article does not report measurements of asbestos exposure.

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: Data article: a laboratory and computer (bioinformatics) re-analysis of a microRNA microarray dataset the authors had published earlier (GSE59180), using different data processing and clustering methods
• Who was studied: 16 preserved (formalin-fixed paraffin-embedded) tumour samples from malignant pleural mesothelioma patients in Sydney, Australia, who had extrapleural pneumonectomy: 8 long survivors (median 53.7 months) and 8 short survivors (median 6.4 months). 75% were male, with 2 women in each group. None had prior chemotherapy. Dates are not given.
• Exposure: The article does not report measurements of asbestos exposure. The study compared tumour microRNA expression between long-term and short-term survivors who had not received prior chemotherapy.
• Main results:
  • Two clusters of microRNAs differed between long and short survivors. Cluster 1 held 15 microRNAs higher in short survivors; cluster 11 held 15 microRNAs lower in short survivors.
  • Example from cluster 1: hsa-miR-221-3p was 6.45867-fold higher in short survivors than in long survivors (p = 0.0029257).
  • The authors reported that the direction of change of the candidate microRNAs agreed with their earlier miR-Score study.
  • Predicted gene targets of the candidate microRNAs were examined in three pathways: PI3K/Akt signaling, hippo signaling and focal adhesion.
  • In the pathway table, hippo signaling had an enrichment score of 6.25988 and p-value of 0.00191147, with 8 genes from the list.
  • The gene CCND2, a predicted target of hsa-miR-17-5p, appeared in all three of these pathways.
  • Using the ChIPBase database, the authors found that the regulator Jun/AP1 binds to the promoter regions of 13 microRNAs, including hsa-miR-17, hsa-miR-20a and hsa-miR-210.
• The authors' conclusion: The authors concluded that these additional analyses supported their previous observations (the miR-Score survival signature). They also concluded that identifying enriched binding motifs and biological themes has merit in prioritizing genes for further validation.
• Limitations the authors state:
  • Gene targets were predicted by computer databases. The authors said known pitfalls remain and they proceeded with caution.
  • The statistical test (one-way ANOVA) assumed that expression patterns were normally distributed and that variance was about equal between groups.
  • The analysis had to adjust for technical problems, including the shortcomings of extracting RNA from preserved (FFPE) tissue blocks.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Mesothelium, Prognosis, Median Survival, EGFR, Cisplatin, Pemetrexed (Alimta), Bevacizumab.

Related studies

• MiR-score: a novel 6-microRNA signature that predicts survival outcomes in patients with malignant pleural mesothelioma — M.B. Kirschner, Y.Y. Cheng, et al. (2015)
• Analysis of microRNA expression signatures in malignant pleural mesothelioma, pleural inflammation, and atypical mesothelial hyperplasia reveals common predictive tumorigenesis-related targets — E.G. Ramírez-Salazar, L.C. Salinas-Silva, et al. (2014)
• Tumor Suppressor microRNAs Contribute to the Regulation of PD-L1 Expression in Malignant Pleural Mesothelioma — S.C. Kao, Y.Y. Cheng, et al. (2017)
• Dysregulated Expression of the MicroRNA miR-137 and Its Target YBX1 Contribute to the Invasive Characteristics of Malignant Pleural Mesothelioma — T.G. Johnson, K. Schelch, et al. (2018)
• Osteopontin modulates inflammation, mucin production, and gene expression signatures after inhalation of asbestos in a murine model of fibrosis — T. Sabo-Attwood, M.E. Ramos-Nino, et al. (2011)
• Towards a potential pan-cancer prognostic signature for gene expression based on probesets and ensemble machine learning — D. Chicco, A. Alameer, et al. (2022)

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