Abstract
Soluble mesothelin-related peptide (SMRP) is a promising biomarker for malignant pleural mesothelioma (MPM), but several confounding factors can reduce SMRP-based test’s accuracy. The identification of these confounders could improve the diagnostic performance of SMRP. In this study, we evaluated the sequence of 1,000 base pairs encompassing the minimal promoter region of the MSLN gene to identify expression quantitative trait loci (eQTL) that can affect SMRP. We assessed the association between four MSLN promoter variants and SMRP levels in a cohort of 72 MPM and 677 non-MPM subjects, and we carried out in vitro assays to investigate their functional role. Our results show that rs2235503 is an eQTL for MSLN associated with increased levels of SMRP in non-MPM subjects. Furthermore, we show that this polymorphic site affects the accuracy of SMRP, highlighting the importance of evaluating the individual’s genetic background and giving novel insights to refine SMRP specificity as a diagnostic biomarker.
Highlights
Malignant pleural mesothelioma (MPM) is a highly aggressive and rare cancer of the pleura triggered by exposure to asbestos and associated with a poor prognosis (Bianchi et al, 2017)
Our previous data showed that single nucleotide polymorphisms (SNPs) within regulatory regions of the MSLN gene were associated with soluble mesothelin-related peptide” (SMRP) levels, raising the question of whether the evaluation of these variants could improve the performance of SMRP in the diagnosis of MPM (Garritano et al, 2014; De Santi et al, 2017)
We found that two haplotypes (#2 and #3) of the minimal promoter region of the MSLN gene were associated with increased serum levels of SMRP in non-MPM subjects
Summary
Malignant pleural mesothelioma (MPM) is a highly aggressive and rare cancer of the pleura triggered by exposure to asbestos and associated with a poor prognosis (Bianchi et al, 2017). The plasmatic concentration of SMRP is measurable from blood samples, and it is usually higher in MPM than in nonMPM subjects (either healthy or affected by other respiratory conditions), allowing fair discrimination between these two groups (Gao et al, 2019; Gillezeau et al, 2019). Despite these promising features, several confounding factors can reduce the accuracy of SMRP as a diagnostic biomarker, thereby preventing its employment in the clinical practice. Our results show that evaluating the individual’s genotype to establish personalized cutoff values can increase the diagnostic accuracy of SMRP, thereby helping to promote its translation into clinical practice
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