Profiling Tumor-Associated Markers for Early Detection of Malignant Mesothelioma: An Epidemiologic Study

Abstract

Improved detection methods for diagnosis of asymptomatic malignant mesothelioma (MM) are essential for an early and reliable detection and treatment of this type of neoplastic disease. Thus, focus has been on finding tumor markers in the blood that can be used for noninvasive detection of MM. Ninety-four asbestosexposed subjects defined at high risk, 22 patients with MM, and 54 healthy subjects were recruited for evaluation of the clinical significance of 8-hydroxy-2 ¶-deoxyguanosine (8OHdG) in WBCs and plasma concentrations of soluble mesothelin-related peptides (SMRPs), angiogenic factors [platelet-derived growth factor B, hepatocyte growth factor, basic fibroblast growth factor, and vascular endothelial growth factor B (VEGFB)], and matrix proteases [matrix metalloproteinase (MMP) 2, MMP9, tissue inhibitor of metalloproteinase (TIMP) 1, and TIMP2] for potential early detection of MM. The area under receiver operating characteristic (ROC) curves indicate that 8OHdG levels can discriminate asbestosexposed subjects from healthy controls but not from MM patients. Significant area under ROC curve values were found for SMRPs, discriminating asbestos-exposed subjects from MM patients but not from healthy controls. Except for platelet-derived growth factor B, the hepatocyte growth factor, basic fibroblast growth factor, and VEGFB can significantly differentiate high-risk individuals from healthy control and cancer groups. No diagnostic value was observed for MMP2, MMP9, TIMP1, and TIMP2. In addition to the diagnostic performance defined by the ROC analysis, the sensitivity and specificity results of markers with clinical significance were calculated at defined cutoffs. The combination of 8OHdG, VEGFB, and SMRPs best distinguished the individual groups, suggesting a potential indicator of early and advanced MM cancers. The combination of blood biomarkers and radiographic findings could be used to stratify the risk of mesothelioma in asbestos-exposed populations.

Clinical utility of diagnostic markers for malignant pleural mesothelioma

“…Surgery resulted in a sharp decrease in serum mesothelin while chemotherapy induced no change [67]. A significantly larger series from France confirmed the diagnostic utility of mesothelin [69,70] followed by similar results in series from Italy [71,72] and Netherlands [24]. Globally analysed, the results from these different teams showed that serum mesothelin is a good diagnostic marker with areas under ROC curved around 0.8-0.85.…”

“…Data from literature shows that in asbestos exposed subjects serum mesothelin is only marginally but not significantly increased over normal unexposed subjects [71] and there seems to be no increase over time [79]. Roe et al showed in a small series of 47 malignant mesothelioma for which they had available at least one serum sample, sampled between 6 months and 30 years before diagnosis that there is no significant elevation of serum mesothelin which could be useful for early mesothelioma diagnosis [80].…”

Effectiveness of mesothelin family proteins and osteopontin for malignant mesothelioma

“…The resulting sub-group could thereby be subject to a more dedicated medical follow-up (i.e. more frequent diagnostic exams) [32,43].…”

Biomarkers in the prevention and follow-up of workers exposed to asbestos

“…The term "soluble mesothelin-related peptides" (SMRP) refers to a number of similar proteins deriving from subsequent cleavages of cell-surface precursor. SMRP has been found to be able to discriminate between epithelioid MPM histotype (8), and controls with a high specificity (80-85%), though with less consistent sensitivity (60-90%) (9)(10)(11). Diagnostic performance of SMRP may be influenced by the prevalence of specific genetic polymorphisms within the MSLN gene.…”