Diagnostic value of microRNAs in asbestos exposure and malignant mesothelioma: systematic review and qualitative meta-analysis

Our plain-English summary of Diagnostic value of microRNAs in asbestos exposure and malignant mesothelioma: systematic review and qualitative meta-analysis, by L. Micolucci, M.M. Akhtar, F. Olivieri, et al (Oncotarget, 2016).

The study

• Authors: L. Micolucci, M.M. Akhtar, F. Olivieri, M.R. Rippo, A.D. Procopio
• Journal: Oncotarget
• Published: 2016;7(36):58606-58637
• Type of article: Meta-analysis, Systematic review
• Cited by: 62 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Asbestos is a harmful and exceptionally persistent natural material. Malignant mesothelioma (MM), an asbestos-related disease, is an insidious, lethal cancer that is poorly responsive to current treatments. Minimally invasive, specific, and sensitive biomarkers providing early and effective diagnosis in high-risk patients are urgently needed. MicroRNAs (miRNAs, miRs) are endogenous, non-coding, small RNAs with established diagnostic value in cancer and pollution exposure. A systematic review and a qualitative meta-analysis were conducted to identify high-confidence miRNAs that can serve as biomarkers of asbestos exposure and MM.

Methods: The major biomedical databases were systematically searched for miRNA expression signatures related to asbestos exposure and MM. The qualitative meta-analysis applied a novel vote-counting method that takes into account multiple parameters. The most significant miRNAs thus identified were then subjected to functional and bioinformatic analysis to assess their biomarker potential.

Results: A pool of deregulated circulating and tissue miRNAs with biomarker potential for MM was identified and designated as "mesomiRs" (MM-associated miRNAs). Comparison of data from asbestos-exposed and MM subjects found that the most promising candidates for a multimarker signature were circulating miR-126-3p, miR-103a-3p, and miR-625-3p in combination with mesothelin. The most consistently described tissue miRNAs, miR-16-5p, miR-126-3p, miR-143-3p, miR-145-5p, miR-192-5p, miR-193a-3p, miR-200b-3p, miR-203a-3p, and miR-652-3p, were also found to provide a diagnostic signature and should be further investigated as possible therapeutic targets.

Conclusion: The qualitative meta-analysis and functional investigation confirmed the early diagnostic value of two miRNA signatures for MM. Large-scale, standardized validation studies are needed to assess their clinical relevance, so as to move from the workbench to the clinic.

In plain English

This article was a systematic review with a 'qualitative meta-analysis' of published research on microRNAs (small RNA molecules) as possible markers of asbestos exposure and malignant mesothelioma. The authors searched three databases up to 29 September 2015 and kept 39 articles. They analyzed 30 and only reviewed 9 that were based on laboratory function tests. No studies of peritoneal or pericardial mesothelioma were available, so all the mesothelioma-associated microRNAs refer to pleural mesothelioma. Simply counting how often each microRNA was reported did not identify a signature, partly because studies differed widely. The authors then scored 41 microRNAs that had been confirmed by a lab test (qRT-PCR). They picked nine tissue microRNAs, all lower in mesothelioma than in healthy subjects, and five blood microRNAs. In pooled data comparing mesothelioma patients with asbestos-exposed subjects, miR-103a-3p combined with mesothelin had a sensitivity of 0.90 (95% CI 0.82-0.96). The authors concluded their process yielded a reliable list of candidates but that large-scale, standardized validation is required. They noted that few raw datasets were available and that studies may have judged asbestos exposure differently.

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: Systematic review and qualitative meta-analysis of published studies, using a specially devised vote-counting method, plus pooled diagnostic-accuracy statistics for the main blood microRNAs
• Who was studied: Published studies found in PubMed, GEO DataSet and EMBL-EBI ArrayExpress (last accessed 29 September 2015). Of 39 articles reporting microRNA changes in malignant mesothelioma, 30 went into the qualitative meta-analysis and 9 functional-assay papers were only reviewed. No studies of peritoneal or pericardial mesothelioma were available, so all mesothelioma-associated microRNAs in the review refer to pleural mesothelioma.
• Exposure: Asbestos exposure in general (no fiber types analyzed). Specimens came from mesothelioma patients, asbestos-exposed subjects and healthy controls. The authors state that studies used different criteria for deciding who was exposed.
• Main results:
  • No studies of peritoneal or pericardial mesothelioma were available, so all mesothelioma-associated microRNAs in the review refer to pleural mesothelioma.
  • Simple vote counting across studies did not identify microRNA signatures able to distinguish specimens from mesothelioma or asbestos-exposed subjects from those of controls.
  • Among 41 qRT-PCR-confirmed microRNAs, the scoring method picked 9 tissue microRNAs (miR-145-5p, miR-126-3p, miR-16-5p, miR-192-5p, miR-193a-3p, miR-200b-3p, miR-203-3p, miR-143-3p, miR-652-3p). All were lower in mesothelioma than in healthy subjects.
  • The meta-analysis picked five circulating (blood) microRNAs. Four were measured in plasma or serum (miR-126-3p, miR-29c-5p, miR-92a-3p, miR-625-3p) and one in the blood-cell fraction (miR-103a-3p). miR-126-3p and miR-103a-3p scored highest.
  • Of 15 circulating microRNAs reported in mesothelioma, 9 are commonly found in healthy individuals but changed in mesothelioma. The other 6, including miR-625-3p, were found only in the mesothelioma set.
  • For circulating microRNAs in diagnosing mesothelioma, the pooled area under the summary ROC curve was 0.8563.
  • Single microRNAs compared against asbestos-exposed subjects had a sensitivity of 0.79 (95% CI 0.71-0.85) and a specificity of 0.72 (95% CI 0.67-0.78). Compared against healthy subjects, sensitivity was 0.78 (0.68-0.87) and specificity 0.69 (0.59-0.77).
  • miR-103a-3p combined with mesothelin, with asbestos-exposed subjects as the reference group, had a sensitivity of 90% (0.82-0.96) and a diagnostic odds ratio of 46.65 (18.94-114.9). Specificity is printed as 82.7% (0.74-0.89) in the text but as 0.88 in Table 4. The authors said the combination performed better than mesothelin alone or single microRNAs.
• The authors' conclusion: The authors concluded that their process yielded a reliable list of mesothelioma-associated microRNA candidates: a nine-microRNA tissue signature and a blood panel of miR-126-3p, miR-103a-3p, miR-625-3p and mesothelin. They said large-scale, standardized validation is required to establish whether these can deliver accurate diagnoses and identify high-risk patients.
• Limitations the authors state:
  • Few raw datasets on mesothelioma microRNA expression were available online, so a broad statistical approach was not possible.
  • The studies differed in sample types, controls, lab methods and statistics, which hampered comparison. Significant heterogeneity was found between studies.
  • Studies may have used different criteria to classify exposed and non-exposed people, so the groups are not strictly comparable.
  • MicroRNAs could not be ranked by sample numbers or average fold changes because most papers did not provide this information.
  • Only one study addressed microRNAs in asbestos-related lung cancers, so no conclusions could be drawn there.
  • Data were insufficient to tell whether the miR-103a-3p blood-cell findings reflect cancer or ordinary blood-cell behavior.

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: Asbestos Exposure, Malignant Mesothelioma, Systematic Review, Meta-Analysis, Biomarker, Mesothelin.

Related studies

• Progress of research on microRNAs with diagnostic value in asbestos exposure: A call for method standardization — L. Micolucci, M.R. Rippo, et al. (2017)
• MicroRNAs diagnostic and prognostic value as predictive markers for malignant mesothelioma — E. Sturchio, M.G. Berardinelli, et al. (2020)
• MicroRNA signature of malignant mesothelioma with potential diagnostic and prognostic implications — S. Busacca, S. Germano, et al. (2010)
• Downregulated microRNAs in the differential diagnosis of malignant pleural mesothelioma — G.V. Gee, D.C. Koestler, et al. (2010)
• A diagnostic assay based on microRNA expression accurately identifies malignant pleural mesothelioma — H. Benjamin, D. Lebanony, et al. (2010)
• Diagnostic value of soluble mesothelin-related peptides for malignant mesothelioma: a meta-analysis — L. Luo, H.Z. Shi, et al. (2010)

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