Combined circulating epigenetic markers to improve mesothelin performance in the diagnosis of malignant mesothelioma

Our plain-English summary of Combined circulating epigenetic markers to improve mesothelin performance in the diagnosis of malignant mesothelioma, by L. Santarelli, S. Staffolani, E. Strafella, et al (Lung Cancer, 2015).

The study

• Authors: L. Santarelli, S. Staffolani, E. Strafella, L. Nocchi, N. Manzella, P. Grossi, M. Bracci, E. Pignotti, R. Alleva, B. Borghi, C. Pompili, A. Sabbatini, C. Rubini, L. Zuccatosta, E. Bichisecchi, M. Valentino, K. Horwood, M. Comar, M. Bovenzi, L.F. Dong, J. Neuzil, M. Amati, M. Tomasetti
• Journal: Lung Cancer
• Published: 2015;90(3):457-64
• Cited by: 44 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Objectives: Malignant mesothelioma (MM) is a highly aggressive tumor with poor prognosis. A major challenge is the development and application of early and highly reliable diagnostic marker(s). Serum biomarkers, such as 'soluble mesothelin-related proteins' (SMRPs), is the most studied and frequently used in MM. However, the low sensitivity of SMRPs for early MM limits its value; therefore, additional biomarkers are required. In this study, two epigenetically regulated markers in MM (microRNA-126, miR-126, and methylated thrombomodulin promoter, Met-TM) were combined with SMRPs and evaluated as a potential strategy to detect MM at an early stage.

Materials And Methods: A total of 188 subjects, including 45 MM patients, 99 asbestos-exposed subjects, and 44 healthy controls were prospectively enrolled, serum samples collected, and serum levels of SMRPs, miR-126 and Met-TM evaluated. Logistic regression analysis was performed to evaluate the diagnostic value of the three biomarkers. Using this approach, the performance of the '3-biomarker classifier' was tested by calculating the overall probability score of the MM and control samples, respectively, and the ROC curve was generated.

Results And Conclusion: The combination of the three biomarkers was the best predictor to differentiate MM patients from asbestos-exposed subjects and healthy controls. The accuracy and cancer specificity was confirmed in a second validation cohort and lung cancer population. We propose that the combination of the two epigenetic biomarkers with SMRPs as a diagnosis for early MM overcomes the limitations of using SMRPs alone.

Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

In plain English

This Italian study tested whether two gene-regulation blood markers, microRNA-126 (miR-126) and methylated thrombomodulin (Met-TM), add to soluble mesothelin-related proteins (SMRPs), an established mesothelioma blood marker. The authors measured all three in serum from 45 mesothelioma patients, 99 asbestos-exposed people and 44 unexposed healthy controls. SMRPs and Met-TM were higher in patients. miR-126 was lower in both patients and exposed people than in controls. Used alone, SMRPs separated patients from controls with 60% sensitivity and 89% specificity. Combining the three markers slightly raised the area under the curve, a measure of test accuracy, from 0.818 (95% CI 0.723 to 0.914) to 0.857 (95% CI 0.767 to 0.927). These ranges overlap, and no statistical comparison of the two was reported. A second group was tested: 18 patients, 50 exposed people, 20 controls and 42 lung cancer patients. There, mesothelioma patients mostly had high SMRPs plus at least one altered epigenetic marker. The authors stated their data cannot show early detection, because they lacked serum samples collected over time. They concluded the added markers reduce false-negative and false-positive SMRP results.

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: Diagnostic blood-biomarker study comparing mesothelioma patients, asbestos-exposed subjects and healthy controls, using ROC curves and logistic regression, with a second validation cohort and a lung cancer group
• Who was studied: Main cohort of 188: 45 malignant mesothelioma patients (diagnosed on pleural biopsies; 33 epithelial, 9 sarcomatoid, 3 mixed-type) recruited November 2008 to January 2013 at the University Hospital of Ancona, Italy; 99 asbestos-exposed subjects followed by the Center for Occupational Medicine (2004 to 2013); 44 healthy controls never exposed to asbestos. Validation cohort from the University of Trieste: 18 MM patients, 50 asbestos-exposed subjects, 20 controls. Separate group of 42 lung cancer patients.
• Exposure: The asbestos-exposed group were ship builders, machine operators, electricians, pipe fitters and construction workers, or their family members. Exposure was expressed as cumulative fibers ((ff/cm3) × yrs): mean 232 (SD 414) in MM patients and 483 (SD 748) in exposed subjects. Fiber types were not named. The markers studied were serum SMRPs, miR-126 and Met-TM.
• Main results:
  • SMRPs and Met-TM were higher in the serum of MM patients than in asbestos-exposed subjects and healthy controls.
  • miR-126 was lower in MM patients and in asbestos-exposed subjects than in healthy controls.
  • SMRPs were higher in the epithelioid subtype and fell after surgical removal of the tumor. The two epigenetic markers were not affected by tumor removal or tumor subtype.
  • Used alone, SMRPs distinguished MM patients from controls with 60% sensitivity and 89% specificity.
  • miR-126 alone distinguished MM patients from controls with 75% sensitivity but 54% specificity. Met-TM alone had 82% specificity.
  • The 3-biomarker model slightly increased the AUC compared with SMRPs alone: 0.857 (95% CI, 0.767 to 0.927) versus 0.818 (95% CI, 0.723 to 0.914). The intervals overlap, and no statistical comparison of the two AUCs is reported.
  • A significant risk of disease (odds greater than 4.0) was found when high SMRPs occurred with one altered epigenetic marker (combinations 6 and 7). Altered levels of both epigenetic markers increased risk even at low SMRP levels (combination 4).
  • In the validation cohort, MM patients fell within combinations 6 to 8 (high SMRPs plus at least one or both altered epigenetic markers). Asbestos-exposed subjects and controls mainly fell into low-SMRP combinations. Lung cancer patients mainly fell into combinations 3 and 4.
  • Among MM patients, SMRP levels were associated with worse prognosis, while miR-126 levels were reported as predictive of better prognosis.
• The authors' conclusion: The authors concluded that adding the two epigenetic serum markers to SMRPs is a considerable improvement over current diagnostic approaches and reduces false-negative and false-positive SMRP tests. They also stated that their data cannot show the combination detects MM early.
• Limitations the authors state:
  • The authors stated that, because they lacked serum samples collected prospectively over time, their data cannot support a conclusion that the combination detects MM early.

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: Mesothelin, Malignant Mesothelioma, Prognosis, Biomarker, Soluble Mesothelin-Related Peptides (SMRP), Lung Cancer.

Related studies

• Association of MiR-126 with soluble mesothelin-related peptides, a marker for malignant mesothelioma — L. Santarelli, E. Strafella, et al. (2011)
• Circulating epigenetic biomarkers in lung malignancies: From early diagnosis to therapy — M. Tomasetti, M. Amati, et al. (2017)
• Combination of MiR-103a-3p and mesothelin improves the biomarker performance of malignant mesothelioma diagnosis — D.G. Weber, S. Casjens, et al. (2014)
• Clinical significance of circulating miR-126 quantification in malignant mesothelioma patients — M. Tomasetti, S. Staffolani, et al. (2012)
• Mesothelin and osteopontin as circulating markers of diffuse malignant peritoneal mesothelioma: A preliminary study — F. Bruno, D. Baratti, et al. (2018)
• The relationship between tumor MSLN methylation and serum mesothelin (SMRP) in mesothelioma — H.H. Nelson, L.M. Almquist, et al. (2011)

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