Serum Extracellular Vesicle-Derived microRNAs as Potential Biomarkers for Pleural Mesothelioma in a European Prospective Study

Our plain-English summary of Serum Extracellular Vesicle-Derived microRNAs as Potential Biomarkers for Pleural Mesothelioma in a European Prospective Study, by E. Casalone, G. Birolo, B. Pardini, et al (Cancers, 2022).

The study

• Authors: E. Casalone, G. Birolo, B. Pardini, A. Allione, A. Russo, C. Catalano, M. Mencoboni, D. Ferrante, C. Magnani, M. Sculco, I. Dianzani, F. Grosso, D. Mirabelli, R.A. Filiberti, O. Rena, C. Sacerdote, M. Rodriguez-Barranco, K. Smith-Byrne, S. Panico, C. Agnoli, T. Johnson, R. Kaaks, R. Tumino, J.M. Huerta, E. Riboli, A.K. Heath, C. Trobajo-Sanmartín, M.B. Schulze, C. Saieva, P. Amiano, A. Agudo, E. Weiderpass, P. Vineis, G. Matullo
• Journal: Cancers
• Published: 2022;15(1)
• Cited by: 11 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer with a dismal prognosis. Early therapeutic interventions could improve patient outcomes. We aimed to identify a pattern of microRNAs (miRNAs) as potential early non-invasive markers of MPM. In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition cohort, we screened the whole miRNome in serum extracellular vesicles (EVs) of preclinical MPM cases. In a subgroup of 20 preclinical samples collected five years prior MPM diagnosis, we observed an upregulation of miR-11400 (fold change (FC) = 2.6, adjusted p-value = 0.01), miR-148a-3p (FC = 1.5, p-value = 0.001), and miR-409-3p (FC = 1.5, p-value = 0.04) relative to matched controls. The 3-miRNA panel showed a good classification capacity with an area under the receiver operating characteristic curve (AUC) of 0.81 (specificity = 0.75, sensitivity = 0.70). The diagnostic ability of the model was also evaluated in an independent retrospective cohort, yielding a higher predictive power (AUC = 0.86). A signature of EV miRNA can be detected up to five years before MPM; moreover, the identified miRNAs could provide functional insights into the molecular changes related to the late carcinogenic process, preceding MPM development.

In plain English

In a case-control study nested in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, the authors sequenced microRNAs carried in tiny particles (extracellular vesicles) in stored blood serum. The serum came from 82 people who later developed malignant pleural mesothelioma and 82 matched cancer-free controls. Comparing 80 cases with 80 controls, they found no significant difference in microRNA levels. In 20 cases whose blood was taken within five years before diagnosis, miR-11400 was significantly higher than in matched controls. miR-148a-3p and miR-409-3p were higher only before correction for multiple testing. A laboratory re-test (RT-qPCR) showed the same direction, but the differences were not statistically significant. A score combining the three microRNAs had an area under the curve (AUC) of 0.81, with sensitivity 75% and specificity 70%, in the EPIC subgroup. In a separate northern Italian group of 30 already-diagnosed asbestos-exposed patients and 20 asbestos-exposed controls, the same score had an AUC of 0.86, with sensitivity 53% and specificity 95%. The authors concluded the signature is a potential marker that needs replication in other prospective cohorts. They noted the small number of cases as a limitation.

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: Case-control study nested in a prospective cohort (EPIC), with microRNA sequencing of serum extracellular vesicles, plus testing of the resulting model in a separate retrospective case-control group
• Who was studied: 148 EPIC participants developed malignant pleural mesothelioma by the 2016 follow-up. Serum was available for 82 of them, each matched to one cancer-free control from the same centre by age at blood collection, sex and asbestos exposure. The samples came from six countries: Germany, Spain, France, Italy, the Netherlands and the United Kingdom. Diagnosis followed blood collection by 17 days to 18 years (median 8 years). A subgroup of 24 cases was diagnosed within five years of blood collection, and 20 of these, with their matched controls, had an asbestos exposure assessment. The separate retrospective group was 30 asbestos-exposed patients diagnosed with malignant pleural mesothelioma in 2018 to 2019 in Novara, plus 20 asbestos-exposed cancer-free controls, all from northern Italy.
• Exposure: The study measured microRNAs in serum extracellular vesicles. Asbestos exposure was used for matching and adjustment, not as the exposure under study. An expert epidemiologist assessed asbestos exposure from occupational history for 58 cases. Among the 82 cases, 40 were exposed, 18 unexposed and 24 had no data. The article does not name fiber types.
• Main results:
  • In the analysis of 80 prospectively collected cases and 80 controls, no significant difference in microRNA expression was found.
  • In the 20 cases whose blood was taken within five years before diagnosis, miR-11400 was significantly higher than in matched controls after correction for multiple testing (FDR = 0.01; log2 fold change 1.4; 95% CI 0.69 to 2.0).
  • In the same five-year subgroup, three microRNAs differed only at the nominal (uncorrected) p-value. miR-148a-3p was higher (log2 fold change 0.6; p = 0.001; 95% CI 0.2, 0.82). miR-409-3p was higher (log2 fold change 0.7; p = 0.04; 95% CI 0.02, 1.3). miR-4508 was lower (log2 fold change minus 0.7; p = 0.01). miR-4508 was not carried forward because the laboratory probe design failed.
  • Laboratory re-testing (RT-qPCR) of miR-11400, miR-148a-3p and miR-409-3p in the five-year subgroup agreed with the sequencing in direction. The differences between cases and controls were not statistically significant.
  • A model combining the three microRNAs distinguished cases diagnosed within five years from matched controls with an AUC of 0.81, sensitivity 75% and specificity 70%.
  • In the independent retrospective group of 30 diagnosed patients and 20 controls, the model had an AUC of 0.86, sensitivity 53% and specificity 95%.
• The authors' conclusion: The authors concluded that the study identified a potential extracellular vesicle microRNA signature in preclinical malignant pleural mesothelioma up to five years before diagnosis, which raises the possibility of early intervention if the finding is replicated in other prospective cohorts.
• Limitations the authors state:
  • The small number of prospectively collected cases limits the robustness of the results.
  • EPIC took only one blood sample per person, so a sample from no more than five years before diagnosis was available for only some cases.
  • No prospective validation cohort was available. The panel was tested in a case-control setting, which measured sensitivity and specificity at the time of diagnosis rather than in the pre-clinical phase.

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Pleural Mesothelioma, Prognosis, Case-Control Study, P-Value, Carcinogenic.

Related studies

• 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)
• Small and Large Extracellular Vesicles Derived from Pleural Mesothelioma Cell Lines Offer Biomarker Potential — T. Ahmadzada, A. Vijayan, et al. (2023)
• Small Extracellular Vesicle-Derived Circular RNA hsa_circ_0007386 as a Biomarker for the Diagnosis of Pleural Mesothelioma — S. Zhand, J. Liao, et al. (2024)
• Peripheral Blood DNA Methylation as Potential Biomarker of Malignant Pleural Mesothelioma in Asbestos-Exposed Subjects — S. Guarrera, C. Viberti, et al. (2019)
• Extracellular vesicles as biomarkers in malignant pleural mesothelioma: A review — T. Ahmadzada, S. Kao, et al. (2020)
• New DNA Methylation Signals for Malignant Pleural Mesothelioma Risk Assessment — G. Cugliari, A. Allione, et al. (2021)

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