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

• Published in: Lung cancer (Amsterdam, Netherlands) Vol. 90; no. 3; pp. 457 - 464
• Main Authors: Santarelli, Lory, Staffolani, Sara, Strafella, Elisabetta, Nocchi, Linda, Manzella, Nicola, Grossi, Paola, Bracci, Massimo, Pignotti, Elettra, Alleva, Renata, Borghi, Battista, Pompili, Cecilia, Sabbatini, Armando, Rubini, Corrado, Zuccatosta, Lina, Bichisecchi, Elisabetta, Valentino, Matteo, Horwood, Keith, Comar, Manola, Bovenzi, Massimo, Dong, Lan-Feng, Neuzil, Jiri, Amati, Monica, Tomasetti, Marco
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.12.2015
• Subjects: Aged; Biomarkers, Tumor; DNA Methylation; Early diagnosis; Epigenesis, Genetic; Epigenetic biomarkers; Female; GPI-Linked Proteins - blood; GPI-Linked Proteins - genetics; Hematology, Oncology and Palliative Medicine; Humans; Lung cancer; Lung Neoplasms - blood; Lung Neoplasms - diagnosis; Lung Neoplasms - etiology; Lung Neoplasms - genetics; Lung Neoplasms - therapy; Male; Mesothelin; Mesothelioma; Mesothelioma - blood; Mesothelioma - diagnosis; Mesothelioma - etiology; Mesothelioma - genetics; Mesothelioma - therapy; Mesothelioma, Malignant; Methylated gene thrombomodulin; MicroRNAs - blood; MicroRNAs - genetics; Middle Aged; miR-126; Multidrug Resistance-Associated Proteins - blood; Prognosis; Pulmonary/Respiratory; Reproducibility of Results; MM; EGFL7; Early diagnosis; Met-TM; Cf; Lung cancer; ROC; Methylated gene thrombomodulin; Mesothelioma; Epigenetic biomarkers; SMRPs; AUC; miR-126; LC; Mesothelin; TM; CCL2; CEA; chemokine (C–C motif) ligand 2; lung cancer; soluble mesothelin-related proteins; area under curve; microRNA-126; methylated thrombomodulin; carcinoembryonic antigen; malignant mesothelioma; EGF-like-domain, multiple 7; thrombomodulin; Receiver operating characteristics; cumulative fibers
• ISSN: 0169-5002; 1872-8332; 1872-8332
• DOI: 10.1016/j.lungcan.2015.09.021

[Display omitted] •MM patients showed high levels of SMRPs and Met-TM and low miR-126.•SMRPs and miR-126, but not Met-TM are prognostic factors for MM.•The 3-biomarker model differentiate MM patients from high-risk and healthy subjects.•Epigenetic biomarkers with SMRPs overcomes the limitations of using SMRPs alone.•The 3-biomarker combination distinguish MM from lung cancer. 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. 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. 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.