MicroRNA Signatures in Malignant Pleural Mesothelioma Effusions

Our plain-English summary of MicroRNA Signatures in Malignant Pleural Mesothelioma Effusions, by K.A. Birnie, C.M. Prêle, A.W.B. Musk, et al (Disease Markers, 2019).

The study

• Authors: K.A. Birnie, C.M. Prêle, A.W.B. Musk, N. de Klerk, Y.C.G. Lee, D. Fitzgerald, R.J.N. Allcock, P.J. Thompson, J. Creaney, B. Badrian, S.E. Mutsaers
• Journal: Disease Markers
• Published: 2019;2019:8628612
• Cited by: 22 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an incurable cancer of the pleura that can be difficult to diagnose. Biomarkers for an easier and/or earlier diagnosis are needed. Approximately 90% of MPM patients develop a pleural effusion (PE). PEs are ideal sources of biomarkers as the fluid would almost always require drainage for diagnostic and/or therapeutic reasons. However, differentiating MPM PE from PE caused by other diseases can be challenging. MicroRNAs are popular biomarkers given their stable expression in tissue and fluid. MicroRNAs have been analysed in PE cytology samples for the diagnosis of MPM but have not been measured in frozen/fresh PE. We hypothesise that microRNAs expressed in PE are biomarkers for MPM. TaqMan OpenArray was used to analyse over 700 microRNAs in PE cells and supernatants from 26 MPMs and 21 other PE-causing diseases. In PE cells, combining miR-143, miR-210, and miR-200c could differentiate MPM with an area under the curve (AUC) of 0.92. The three-microRNA signature could also discriminate MPM from a further 40 adenocarcinomas with an AUC of 0.9887. These results suggest that the expression of miR-143, miR-210, and miR-200c in PE cells might provide a signature for diagnosing MPM.

In plain English

This laboratory study from Perth, Western Australia, tested whether microRNAs (small RNA molecules) in fluid around the lung could help tell malignant pleural mesothelioma (MPM) from other causes of such fluid. The authors screened over 700 microRNAs in cells and fluid from 26 people with MPM, 11 with metastatic adenocarcinoma and 10 with benign disease. Asbestos exposure was not studied. In the cells, seven microRNAs were lower and four higher in MPM. Combining miR-143, miR-210 and miR-200c separated MPM from the other diseases with an area under the curve (AUC, a measure of separation) of 0.92 (95% CI 0.84 to 0.99). In a comparison with adenocarcinoma that added 40 more samples, the combination had an AUC of 0.9887 (95% CI 0.97377 to 1.00000), sensitivity of 92.31% and specificity of 96.08%. The article does not print the sample totals for these figures. Worked out from the group sizes, they fit 26 MPM and 51 adenocarcinoma samples. Findings in the fluid itself did not hold up on retesting. The authors concluded that the three microRNAs are potential biomarkers that need testing in a larger group and may not suit all MPM subtypes.

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: laboratory diagnostic biomarker study comparing microRNA levels in stored pleural effusion samples from patients with MPM, adenocarcinoma and benign disease
• Who was studied: Pleural effusion samples from 26 MPM patients, 11 metastatic adenocarcinoma patients and 10 benign-disease patients, randomly selected from a biobank (Sir Charles Gairdner Hospital, Perth, Western Australia). A further 40 adenocarcinoma effusion samples came from the Australian Mesothelioma Tissue Bank. Of the MPM patients, 88% were male and 65% had the epithelioid subtype. Collection dates were not given.
• Exposure: No asbestos or fiber exposure was assessed. The study measured microRNAs (and mesothelin and fibulin-3 mRNA) in pleural effusion cells and fluid.
• Main results:
  • In MPM effusion cells, compared with adenocarcinoma and benign disease combined, seven microRNAs were significantly lower and four significantly higher (miR-139-5p, miR-210, miR-944 and miR-320).
  • Used alone, miR-200c was the best single discriminator between MPM and the other diseases, with an AUC of 0.79 (95% CI: 0.66, 0.92).
  • Combining miR-200c, miR-210 and miR-143 separated MPM from adenocarcinoma and benign disease combined with an AUC of 0.92 (95% CI: 0.84, 0.99).
  • MicroRNA differences found in the effusion fluid (supernatant) were not confirmed by a second test method (qRT-PCR). The authors judged them unlikely to be useful biomarkers.
  • In effusion cells, mesothelin mRNA did not differ significantly between the groups.
  • Fibulin-3 mRNA was higher in MPM effusion cells and gave an AUC of 0.79 (95% CI: 0.65, 0.93). Adding fibulin-3 to the three microRNAs did not improve the signature. In this reduced sample set (five MPM samples excluded), the microRNA model had an AUC of 0.94 (95% CI: 0.87, 1.00).
  • After an additional 40 adenocarcinoma samples were measured, the three-microRNA combination distinguished MPM from adenocarcinoma with an AUC of 0.9887 (95% CI: 0.97377, 1.00000). The article does not print the sample totals for this calculation.
  • In the same MPM versus adenocarcinoma comparison, sensitivity was 92.31%, specificity 96.08%, positive predictive value 92.31% and negative predictive value 96.08%. Overall, 94.81% of samples were correctly classified. The article does not print the totals. Worked out from the stated group sizes (26 MPM, 11 first-round adenocarcinomas plus 40 more), the percentages fit 26 MPM and 51 adenocarcinoma samples.
  • miR-143 went in opposite directions in the two comparisons. It was higher in MPM than in the adenocarcinomas, but lower in MPM than in the first mixed control group. The authors attributed this to differences in the control groups.
• The authors' conclusion: The authors concluded that miR-200c, miR-210 and miR-143 in effusion cells are potential biomarkers for telling MPM apart from benign and other malignant causes of pleural effusion. They found no useful biomarkers in the effusion fluid.
• Limitations the authors state:
  • The signature needs testing in a larger patient group, likely through a multicentre collaboration.
  • Effusions contain various cell types, so the microRNAs identified may not be specific to MPM cells.
  • The signature may not work for all MPM subtypes, because usually only epithelioid MPM cells are shed into the pleural space.
  • The opposite direction of miR-143 in the two comparisons needs to be addressed in future validation studies.
  • Varying fluid viscosity likely reduced RNA extraction from the effusion fluid and affected the results.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Pleura, Biomarker, Pleural Effusion, Cytology, Adenocarcinoma.

Related studies

• Young investigator challenge: MicroRNA-21/MicroRNA-126 profiling as a novel tool for the diagnosis of malignant mesothelioma in pleural effusion cytology — R. Cappellesso, L. Nicolè, et al. (2016)
• MicroRNA profiling in serous cavity specimens: Diagnostic challenges and new opportunities — L. Nicolè, F. Cappello, et al. (2019)
• Plasmatic extracellular vesicle microRNAs in malignant pleural mesothelioma and asbestos-exposed subjects suggest a 2-miRNA signature as potential biomarker of disease — T. Cavalleri, L. Angelici, et al. (2017)
• 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)
• miR-1254 and miR-574-5p: serum-based microRNA biomarkers for early-stage non-small cell lung cancer — K.M. Foss, C. Sima, et al. (2011)
• Droplet digital PCR as a novel system for the detection of microRNA‑34b/c methylation in circulating DNA in malignant pleural mesothelioma — H. Sato, J. Soh, et al. (2019)

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