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

tObjectives: Malignant mesothelioma (MM) is a highly aggressive tumor with poor prognosis. A majorchallenge is the development and application of early and highly reliable diagnostic marker(s). Serumbiomarkers, such as ‘soluble mesothelin-related proteins’ (SMRPs), is the most studied and frequentlyused in MM. However, the low sensitivity of SMRPs for early MM limits its value; therefore, additionalbiomarkers 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 asa 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 diagnosticvalue of the three biomarkers. Using this approach, the performance of the ‘3-biomarker classifier’ wastested by calculating the overall probability score of the MM and control samples, respectively, and theROC curve was generated.Results and conclusion: The combination of the three biomarkers was the best predictor to differentiateMM patients from asbestos-exposed subjects and healthy controls. The accuracy and cancer specificitywas confirmed in a second validation cohort and lung cancer population. We propose that the combina-tion of the two epigenetic biomarkers with SMRPs as a diagnosis for early MM overcomes the limitationsof using SMRPs alone