Identification of a new potential plasmatic biomarker panel for the diagnosis of malignant pleural mesothelioma

Our plain-English summary of Identification of a new potential plasmatic biomarker panel for the diagnosis of malignant pleural mesothelioma, by L. Ferrari, S. Iodice, L. Cantone, et al (La Medicina del Lavoro, 2022).

The study

• Authors: L. Ferrari, S. Iodice, L. Cantone, B. Dallari, L. Dioni, L. Bordini, A. Palleschi, C. Mensi, A.C. Pesatori
• Journal: La Medicina del Lavoro
• Published: 2022;113(6):e2022052
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Malignant pleural mesothelioma (MPM) is a rare highly aggressive tumor strongly associated with asbestos exposure and characterized by poor prognosis. Currently, diagnosis is based on invasive techniques, thus there is a need of identifying non-invasive biomarkers for early detection of the disease among asbestos-exposed subjects. In the present study, we measured the plasmatic concentrations of Mesothelin, Fibulin-3, and HMGB1 protein biomarkers, and of hsa-miR-30e-3p and hsa-miR-103a-3p Extracellular-Vesicles- embedded micro RNAs (EV-miRNAs). We tested the ability of these biomarkers to discriminate between MPM and PAE subjects alone and in combination.

Methods: the study was conducted on a population of 26 patients with MPM and 54 healthy subjects with previous asbestos exposure (PAE). Mesothelin, Fibulin-3, and HMGB1 protein biomarkers were measured by the enzyme-linked immunosorbent assay (ELISA) technique; the levels of hsa-miR-30e-3p and hsa-miR-103a-3p EV-miRNAs was assessed by quantitative real-time PCR (qPCR).

Results: the most discriminating single biomarker resulted to be Fibulin-3 (AUC 0.94 CI 95% 0.88-1.0; Sensitivity 88%; Specificity 87%). After investigating the different possible combinations, the best performance was obtained by the three protein biomarkers Mesothelin, Fibulin-3, and HMGB1 (AUC 0.99 CI 95% 0.97-1.0; Sensitivity 96%; Specificity 93%).

Conclusions: the results obtained contribute to identifying new potential non-invasive biomarkers for the early diagnosis of MPM in high-risk asbestos-exposed subjects. Further studies are needed to validate the evidence obtained, in order to assess the reliability of the proposed biomarker panel.

In plain English

This Milan, Italy, study measured five blood markers to see how well they separated people with malignant pleural mesothelioma (MPM) from asbestos-exposed people without it. It compared 26 MPM patients with 54 healthy subjects with past occupational asbestos exposure. The markers were three plasma proteins (Mesothelin, Fibulin-3, HMGB1) and two microRNAs carried in extracellular vesicles. Proteins were higher and microRNAs lower in MPM patients. Accuracy was measured as area under the curve (AUC), where 1.0 is perfect. Fibulin-3 alone scored best (AUC 0.94, 95% CI 0.87 to 1.0; sensitivity 88%, specificity 87%). All three proteins together scored 0.99 (95% CI 0.97 to 1.0; sensitivity 96%, specificity 93%). Mesothelin plus Fibulin-3 scored 0.98 (95% CI 0.97 to 1.0; sensitivity 92%, specificity 91%). The difference between the two combinations was not statistically significant, and the authors said HMGB1's added value needs confirmation. No marker differed significantly by tumor stage or type, though the authors said the groups were too small for firm conclusions. The authors concluded the three-protein panel appears promising but, citing small numbers and no independent validation, called for larger studies.

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: Exploratory diagnostic biomarker study comparing MPM patients with asbestos-exposed subjects without the disease, using ROC curve analysis adjusted for gender, age, BMI and smoking
• Who was studied: 26 patients with malignant pleural mesothelioma, enrolled at the Thoracic Surgery Unit of Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy, between October 2013 and August 2016. Also 54 healthy subjects with previous asbestos exposure (PAE), who were in a clinical surveillance program at the same hospital's Occupational Health Unit during the same period. Mean age was 71.3 years in the MPM group and 64.8 years in the PAE group.
• Exposure: Asbestos exposure was assessed by a standardized questionnaire. In the MPM group, 14 of 26 (53.8%) had occupational exposure, 1 (3.8%) had environmental exposure and 11 (42.3%) were unknown. All 54 PAE subjects (100%) had occupational exposure. Fiber types are not specified. The markers measured were plasma Mesothelin, Fibulin-3 and HMGB1, and the extracellular-vesicle microRNAs hsa-miR-30e-3p and hsa-miR-103a-3p.
• Main results:
  • Among single markers, Fibulin-3 discriminated MPM patients from PAE subjects best: 23 true positives, 47 true negatives, sensitivity 88%, specificity 87%, AUC 0.94 (95% CI 0.87, 1.0 in Table 3; the abstract gives 0.88-1.0).
  • Adjusted AUCs for the single markers were 0.94 for Fibulin-3, 0.92 for HMGB1 and 0.88 for Mesothelin.
  • Combining all three proteins gave an AUC of 0.99 (95% CI 0.97-1.0), sensitivity 96% and specificity 93%.
  • The combination of Mesothelin and Fibulin-3 alone gave 24 true positives and 49 true negatives, sensitivity 92%, specificity 91%, and an AUC of 0.98 (95% CI 0.97, 1.0).
  • The AUC difference between the three-protein combination and Mesothelin plus Fibulin-3 was not statistically significant (p equal to 0.674). The authors said the actual improvement from adding HMGB1 needs to be confirmed in a larger study.
  • Mean plasma Mesothelin was 3.8 ng/ml (standard deviation 5.8) in MPM patients versus 0.9 ng/ml (standard deviation 0.5) in PAE subjects. All three proteins were higher in MPM patients.
  • Both microRNAs were lower in MPM patients than in PAE subjects. The two-microRNA signature gave an AUC of 0.90, with lower sensitivity and specificity than in the authors' earlier study.
  • None of the markers showed statistically significant differences by TNM stage or tumor histotype among the MPM patients. The authors cautioned that the small number of subjects in each category prevents any firm conclusion.
• The authors' conclusion: The authors concluded that the combination of plasma Mesothelin, Fibulin-3 and HMGB1 showed the highest ability to tell MPM patients from PAE subjects, and that it appears to be a promising high-specificity biomarker panel for MPM diagnosis. They said it needs confirmation in larger validation studies.
• Limitations the authors state:
  • The authors said the small number of subjects and the absence of subjects with other respiratory diseases (such as lung cancer, benign pleural effusion or asbestosis) prevent definite conclusions.
  • The authors state that MPM patients had a less healthy profile (more smokers, higher BMI, older age). These variables were adjusted for in the analyses.
  • This was an exploratory study, and the combined biomarkers were not validated independently. Validation in larger populations is needed.
  • There were few patients in each stage and histotype group, so no firm conclusions can be drawn about differences by stage or tumor type.

Topics

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

Medical terms in this study, explained in our Lexicon: Biomarker, Pleural Mesothelioma, Asbestos Exposure, Prognosis, Mesothelin, Fibulin-3, High Mobility Group Box 1 (HMGB1).

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)
• Identification of miRNA-103 in the cellular fraction of human peripheral blood as a potential biomarker for malignant mesothelioma--a pilot study — D.G. Weber, G. Johnen, et al. (2012)
• Serum HMGB1 as a Potential Biomarker for Patients with Asbestos-Related Diseases — S. Ying, Z. Jiang, et al. (2017)
• HMGB1 as a Potential Biomarker and Therapeutic Target for Malignant Mesothelioma — Y. Wang, Z. Jiang, et al. (2019)
• Increased circulating miR-625-3p: a potential biomarker for patients with malignant pleural mesothelioma — M.B. Kirschner, Y.Y. Cheng, et al. (2012)
• Circulating microRNA-197-3p as a potential biomarker for asbestos exposure — F. Frontini, I. Bononi, et al. (2021)

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