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

Abstract

BackgroundAsbestos exposure is associated with increased risk of several diseases, including malignant mesothelioma (MM). Cell surface glycoprotein mesothelin is overexpressed in MM and serum soluble mesothelin-related peptides (SMRP) were already proposed as a diagnostic or prognostic biomarker in MM. However, interindividual variability in serum SMRP levels limits the clinical usefulness. Our primary objective was to investigate the influence of MSLN rs1057147 on serum SMRP levels in asbestos-exposed subjects and patients with asbestos-related diseases as well as on survival in MM.Subjects and methodsAmong 782 asbestos-exposed subjects and patients with asbestos-related diseases, 154 had MM. Serum SMRP levels were determined using sandwich enzyme-linked immunosorbent assay. All subjects were genotyped for MSLN rs1057147 polymorphism using competitive allele-specific polymerase chain reaction. Nonparametric tests, logistic and Cox regression were used in statistical analysis to compare different subject groups.ResultsMM patients had significantly higher SMRP levels than all other subjects (p < 0.001). Compared to wild-type MSLN rs1057147 genotype, both heterozygotes and carriers of two polymorphic alleles had significantly higher SMRP levels among subjects without MM (p < 0.001), but not in MM patients (p = 0.424). If genotype information was included, specificity of SMRP increased from 88.5% to 92.7% for the optimal cutoff value. Overall survival was significantly shorter in MM patients carrying at least one polymorphic rs1057147 allele (HR = 1.72, 95% CI = 1.15-2.55, p = 0.008).ConclusionsMSLN genetic variability affects serum SMRP levels and was associated with shorter survival of MM patients. Combination of genetic and serum factors could therefore serve as a better diagnostic or prognostic biomarker in MM patients.

Variation rs2235503 C > A Within the Promoter of MSLN Affects Transcriptional Rate of Mesothelin and Plasmatic Levels of the Soluble Mesothelin-Related Peptide

“…In agreement with our previous studies, we did not observe any association in the cohort of MPM patients (Garritano et al, 2014;De Santi et al, 2017). While we cannot rule out that the lack of association observed in MPM patients could be ascribed to a limited statistical power (n = 72), Goricar et al (2020) recently reported similar results, showing that the minor allele of the rs1057147 was associated with increased SMRP levels in non-MPM (n = 782) but not in MPM subjects (n = 154). Together, these observations seem to corroborate the hypothesis that genotype has only a limited effect on SMRP levels in the malignant context, probably due to the major role played by other cancer-related factors in altering SMRP concentration.…”

“…Thus, likely, the association observed in vivo should be ascribed to other SNPs in LD with haplotype #3 but residing outside the 1,000-bps promoter region herein considered. Since the results from other groups suggest the possibility of a prognostic significance of SMRP-affecting SNPs ( Dipalma et al, 2011 ; Goricar et al, 2020 ), we tested whether genotype and SMRP levels could be predictive of a worse prognosis in our cohort. Our observations seem to rule out this hypothesis.…”

Current Mesothelioma Treatment and Future Perspectives

“…Predictive and prognostic biomarkers are also needed to support the treatment and follow up of patients with MM [17]. It has been shown that apart from clinical characteristics such as C-reactive protein or tumor stage, serum and genetic markers may be associated with treatment outcome in MM [10,[18][19][20][21][22][23][24][25][26][27][28][29]. disease risk, diagnosis and treatment are also emerging [31].…”

Association of genetic variants in the 3′‐untranslated region of the mesothelin (MSLN) gene with ovarian carcinoma

“…The mesothelin (MSLN) precursor protein is a 69‐kDa (630 amino acid residues) that is proteolytically processed into the 29‐kDa megakaryocyte potentiating factor (MPF) and 40‐kDa membrane‐bound mature MSLN using the protease furin at cleavage site Arg295, Figure 1. [ 5,10–12 ] MSLN is supposed to be expressed on the exterior side of multiple cancerous tissues including ovarian carcinoma, [ 13–17 ] gastric adenocarcinoma, [ 18,19 ] colorectal cancer, [ 20 ] malignant mesothelioma, [ 21–24 ] cervical squamous cell carcinoma, [ 25 ] breast carcinoma, [ 26–28 ] uterine carcinoma, [ 29 ] and esophageal adenocarcinoma, [ 30 ] and hence this polypeptide could represent a prognostic indicator for various malignancies.…”

“…Recently, two genetic variants (rs1057147 G > A and rs57272256 C > T) within the 3′‐untranslated region (3′‐UTR) of MSLN gene were identified and associated with the progression of malignant mesothelioma. [ 24,31,32,39 ] Additionally, the MSLN ( rs1057147 ) variant is thought to be associated with increased expression of the soluble MSLN‐related peptide (SMRP) and increased risk of malignant mesothelioma among different ethnic subjects. [ 24,32,39 ] Similarity, our team was interested in designing this case‐control study to evaluate for the first time the association of these two variants at the 3′‐UTR within the MSLN gene with increased risk of ovarian carcinoma among Egyptian women.…”