Biomarkers for Predicting Malignant Pleural Mesothelioma in a Mexican Population

Abstract

Background: Diagnosis of malignant pleural mesothelioma (MPM) remains a challenge, especially when resources in pathology are limited. The study aimed to evaluate cost-effective tumor markers to predict the probability of MPM in plasma samples in order to accelerate the diagnostic workup of the tissue of potential cases.Methods: We conducted a case-control study stratified by gender, which included 75 incident cases with MPM from three Mexican hospitals and 240 controls frequency-matched by age and year of blood drawing. Plasma samples were obtained to determine mesothelin, calretinin, and thrombomodulin using enzyme-linked immunosorbent assays (ELISAs). We estimated the performance of the markers based on the area under the curve (AUC) and predicted the probability of an MPM diagnosis of a potential case based on the marker concentrations.Results: Mesothelin and calretinin, but not thrombomodulin were significant predictors of a diagnosis of MPM with AUCs of 0.90 (95% CI: 0.85-0.95), 0.88 (95% CI: 0.82-0.94), and 0.51 (95% CI: 0.41-0.61) in males, respectively. For MPM diagnosis in men we estimated a true positive rate of 0.79 and a false positive rate of 0.11 for mesothelin. The corresponding figures for calretinin were 0.81 and 0.18, and for both markers combined 0.84 and 0.11, respectively.Conclusions: We developed prediction models based on plasma concentrations of mesothelin and calretinin to estimate the probability of an MPM diagnosis. Both markers showed a good performance and could be used to accelerate the diagnostic workup of tissue samples in Mexico.

Prediagnostic detection of mesothelioma by circulating calretinin and mesothelin – a case-control comparison nested into a prospective cohort of asbestos-exposed workers

“…In previous studies, we have established an assay for the protein marker calretinin and confirmed the results in independent groups of patients from three continents, using a conventional case-control design 26 – 28 . These studies usually enroll patients with more advanced tumor stages and lack prediagnostic samples to assess the performance of markers to detect tumors prior to the occurrence of clinical symptoms 25 .…”

“…Previously, we have tested a combination of calretinin and mesothelin using case-control studies that included symptomatic MM patients, thus with tumors at later stages of development 27 , 28 . Comparing the more sensitive of the two markers with their combination, the increase in sensitivity was relatively small in the Australian/German (14%) and the Mexican study groups (about 13%).…”

“…Concentrations of calretinin in plasma samples were determined by enzyme-linked immunosorbent assays (ELISA), using the Calretinin ELISA kit by DLD Diagnostika GmbH (Hamburg, Germany) according to the manufacturer’s instructions. This assay is based on the same antibodies as used in the previously described version of the calretinin ELISA 26 – 28 , 55 . During the procedure, all reagents and samples were equilibrated to 22 °C and the incubations were performed at 22 °C.…”

Asbestos-Related Diseases and Blood Biomarkers

“…Among the positive immunohistochemical MM markers that can discriminate between malignant and mesothelial cells with the highest sensitivity and specificity are calretinin, cytokeratin5/6, and WT1 [76]. As biomarkers that would enable an earlier noninvasive diagnosis of MM are widely studied, recent studies evaluated if soluble calretinin could also be used as a biomarker in MM [75,[77][78][79][80].…”

“…Studies showed that calretinin was increased in plasma and serum of MM patients compared to patients with other asbestos-related diseases and healthy controls [75,79,80]. Interestingly, patients with asbestosis also had slightly higher serum calretinin compared to patients with pleural plaques [75].…”