Mesothelin Gene Variants Affect Soluble Mesothelin-Related Protein Levels in the Plasma of Asbestos-Exposed Males and Mesothelioma Patients from Germany

SIMPLE SUMMARY: The continuing increase in mortality from malignant mesothelioma, often a late effect of asbestos exposure, has gained much public attention. Malignant mesothelioma is a devastating disease with limited therapeutic options. A major problem is that this cancer is usually diagnosed when the tumor is already large and has spread. An earlier diagnosis could be possible with blood tests that determine biomarkers like the protein mesothelin. The corresponding gene of mesothelin, however, can harbor genetic variants that could influence the proteins blood concentrations. We therefore studied four genetic variants in 410 asbestos-exposed males without cancer and 102 mesothelioma cases and revealed that the mesothelin concentration between the groups was significantly different (p < 0.0001) and that five to eight mutations of the four variants studied were associated with increased mesothelin concentrations (p = 0.001). These results may be a helpful tool to explain unusually high values of mesothelin protein in healthy people and provides a basis to consider the exclusion of influencing factors for an improvement of the diagnostic procedure. Finally, knowledge about confounders can be integrated into surveillance programs offered to high-risk groups of asbestos-exposed workers. ABSTRACT: Malignant mesothelioma (MM) is a severe disease mostly caused by asbestos exposure. Today, one of the best available biomarkers is the soluble mesothelin-related protein (SMRP), also known as mesothelin. Recent studies have shown that mesothelin levels are influenced by individual genetic variability. This study aimed to investigate the influence of three mesothelin (MSLN) gene variants (SNPs) in the 5′-untranslated promoter region (5′-UTR), MSLN rs2235503 C > A, rs3764246 A > G, rs3764247 A > C, and one (rs1057147 G > A) in the 3′-untranslated region (3′-UTR) of the MSLN gene on plasma concentrations of mesothelin in 410 asbestos-exposed males without cancer and 43 males with prediagnostic MM (i.e., with MM diagnosed later on) from the prospective MoMar study, as well as 59 males with manifest MM from Germany. The mesothelin concentration differed significantly between the different groups (p < 0.0001), but not between the prediagnostic and manifest MM groups (p = 0.502). Five to eight mutations of the four SNP variants studied were associated with increased mesothelin concentrations (p = 0.001). The highest mesothelin concentrations were observed for homozygous variants of the three promotor SNPs in the 5′-UTR (p < 0.001), and the highest odds ratio for an elevated mesothelin concentration was observed for MSLN rs2235503 C > A. The four studied SNPs had a clear influence on the mesothelin concentration in plasma. Hence, the analysis of these SNPs may help to elucidate the diagnostic background of patients displaying increased mesothelin levels and might help to reduce false-positive results when using mesothelin for MM screening in high-risk groups.