Mesothelin promoter variants are associated with increased soluble mesothelin-related peptide levels in asbestos-exposed individuals

Abstract

Soluble-Mesothelin Related Peptide (SMRP) is a promising diagnostic biomarker for malignant pleural mesothelioma (MPM), but various confounders hamper its usefulness in surveillance programs. We previously showed that a single nucleotide polymorphism (SNP) within the 3'untranslated region (3'UTR) of mesothelin (MSLN) gene could affect the levels of SMRP. Here, we focused on SNPs located within MSLN promoter and found a strong association between serum SMRP and variant alleles of rs3764247, rs3764246 (that is in strong linkage disequilibrium with rs2235504), and rs2235503 in non-MPM subjects. The inclusion of the genotype information led to an increase in SMRP specificity from 79.9% to 85.5%. Although not statistically significant, the MPM population showed the same trend of association. In order to study the biological role of these SNPs, the promoter region of MSLN was cloned upstream a reporter gene and the four most common haplotypes were compared in a dual luciferase assay. Rs3764247 was shown to have a functional role itself. The other SNPs were shown to interact with each other in a more complex way. Altogether, these data support the idea that SMRP performance is affected by individual (i.e. genetic) variables and that MSLN expression is influenced by SNPs located within the promoter regulatory region.

Evaluation of soluble mesothelin-related peptides and MSLN genetic variability in asbestos-related diseases

“…Similar results were reported for SNPs in the 5' UTR of the MSLN gene that may affect binding of transcription factors: polymorphic alleles were associated with increased SMRP levels only in subjects without MM and accounting for the genotype improved the diagnostic performance of SMRP. 25,26 These results suggest that cutoff values should be redefined taking into account the MSLN genetic variability to facilitate the interpretation of SMRP measurements. 26 For example, a lower cutoff used in subjects with the wild-type genotype would decrease false negative results.…”

“…25,26 These results suggest that cutoff values should be redefined taking into account the MSLN genetic variability to facilitate the interpretation of SMRP measurements. 26 For example, a lower cutoff used in subjects with the wild-type genotype would decrease false negative results.…”

“…Polymorphic alleles of rs3764247 (c.-894A>C), rs3764246 (c.-790A>G), and rs2235503 (c.-340C>A) in the 5' UTR were associated with increased SMRP levels in healthy asbestos-exposed subjects or subjects with benign asbestos-related diseases, but not in MM patients. 25,26 Similarly, rs1057147 (c.*69G>A) in the 3' UTR that affects miR-611 binding was also associated with increased SMRP levels in healthy asbestos-exposed subjects or subjects with benign asbestos-related diseases. 27,28 MSLN genetic variability was thus shown to improve specificity of SMRP as a diagnostic marker and could help redefine and improve the predictive ability of currently used cutoff values.…”

“…27,28 MSLN genetic variability was thus shown to improve specificity of SMRP as a diagnostic marker and could help redefine and improve the predictive ability of currently used cutoff values. 25,26,28 However, no data is available regarding the association of MSLN genetic variability with the prognosis of MM.…”

Overexpressed genes in malignant pleural mesothelioma: implications in clinical management

“…The diagnostic accuracy of mesothelin has been evaluated in several studies (21,(23)(24)(25) and the systematic review and meta-analysis recently performed showed a high specificity (around 89% and 96%) but a low sensitivity (between 32% and 47%) of mesothelin as a diagnostic marker; thus although SMRPs may help to discriminate the MPM from the non-MPM subjects, the sensitivity of the assay is still inadequate (88). In order to better characterize the sensitivity and specificity of SMRP as a biomarker for MPM it should take in consideration that SMRP performance as diagnostic biomarker could be influenced by genetics variants, as show in the recent work by De Santi et al (30) and SNP located in the promoter or in the 3'UTR of MSLN gene could affect protein expression levels (89). SMRPs diagnostic value has been evaluated also in pleural effusion (25,26,29) and it has been observed a higher diagnostic performance in pleural effusion than in serum assessment (22).…”