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

Our plain-English summary of Mesothelin Gene Variants Affect Soluble Mesothelin-Related Protein Levels in the Plasma of Asbestos-Exposed Males and Mesothelioma Patients from Germany, by H.P. Rihs, S. Casjens, I. Raiko, et al (Biology, 2022).

The study

• Authors: H.P. Rihs, S. Casjens, I. Raiko, J. Kollmeier, M. Lehnert, K. Nöfer, K. May-Taube, N. Kaiser, D. Taeger, T. Behrens, T. Brüning, G. Johnen, MoMar Study Group
• Journal: Biology
• Published: 2022;11(12)
• Cited by: 3 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This German study asked whether common inherited variations in the mesothelin (MSLN) gene affect blood levels of mesothelin, a protein studied as a possible blood test for malignant mesothelioma. The authors tested four gene variants (three in the promoter region, one at the gene's end) and measured plasma mesothelin in 512 men. There were three groups: 410 asbestos-exposed men without cancer who had recognized benign asbestos-related diseases; 43 men from the MoMar cohort whose blood was drawn before their mesothelioma was diagnosed; and 59 men with already diagnosed mesothelioma from a Berlin clinic. Using a cut-off of 2.9 nM, 11 controls (2.7%) had false-positive results. Among controls, carrying two copies of a variant was linked to higher odds of a false-positive result. For rs2235503, the age-adjusted odds ratio for AA versus the common CC genotype was 20.68 (95% confidence interval 4.14 to 103.4). Similar associations appeared in the pre-diagnosis cases but not in the already diagnosed cases. The authors concluded that testing these variants may help explain unusually high mesothelin levels. They noted that the number of mesothelioma cases was small.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Genetic association study comparing MSLN gene variants with plasma mesothelin levels, using samples from a prospective asbestos cohort (MoMar) plus clinic-recruited mesothelioma cases
• Who was studied: 512 men in Germany, overall median age 73 years. 410 were asbestos-exposed, cancer-free controls with benign asbestos-related diseases recognized as occupational diseases, randomly selected by age and smoking status from 2769 MoMar participants. 43 were prediagnostic malignant mesothelioma cases from MoMar, with blood drawn a median 8.5 months before diagnosis. 59 were manifest malignant mesothelioma cases recruited at Lungenklinik Heckeshorn in Berlin.
• Exposure: All participants were asbestos-exposed; fiber types and doses were not reported. The factors studied were four MSLN gene variants in relation to plasma mesothelin: rs2235503 C > A, rs3764246 A > G and rs3764247 A > C in the promoter region, and rs1057147 G > A in the 3′-UTR. A level of 2.9 nM or higher counted as a positive test.
• Main results:
  • Controls had lower mesothelin than mesothelioma cases (p less than 0.0001). Manifest cases had slightly higher median mesothelin than prediagnostic cases (1.61 nM vs 1.34 nM), but the difference was not statistically significant (p = 0.502).
  • 11 of 410 controls (2.7%) had a false-positive mesothelin result (2.9 nM or higher).
  • True-positive results occurred in 23.7% of manifest cases and 18.6% of prediagnostic cases. The difference was not statistically significant (p = 0.534).
  • In controls, the age-adjusted odds ratio for a false-positive result with the rs2235503 AA genotype versus the common CC genotype was 20.68 (95% CI 4.14 to 103.4, p less than 0.001).
  • In prediagnostic cases, the odds of a positive result were 33.3-fold higher with rs3764246 GG and 22.7-fold higher with rs3764247 CC, compared with the common genotype. No such increase was seen in manifest cases.
  • Of the 33 samples above the cut-off, 15 (45%) had the three-variant promoter haplotype CGA. In manifest cases, 10 of the 14 who exceeded the cut-off had no variant.
  • The odds of a positive test were higher for mesothelioma cases than for controls (OR 10.44, 95% CI 4.84 to 22.5).
• The authors' conclusion: The authors concluded that determining these SNPs may help explain unusually high soluble mesothelin-related protein levels and could support improved diagnostic procedures.
• Limitations the authors state:
  • The number of mesothelioma cases was relatively small, especially prediagnostic cases. The patterns seen in that subgroup might disappear in a larger group.
  • Prediagnostic mesothelioma cases also showed an accumulation of MSLN variants. In screening, they therefore could not be told apart from cancer-free people with false-positive results.
  • Whether routine genotyping would be practical and cost-effective in clinical practice remains to be determined.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelin, Mesothelioma, Malignant Mesothelioma, Asbestos Exposure, Biomarker, Soluble Mesothelin-Related Peptides (SMRP), Odds Ratio.

Related studies

• Mesothelin promoter variants are associated with increased soluble mesothelin-related peptide levels in asbestos-exposed individuals — C. De Santi, P. Pucci, et al. (2017)
• Soluble mesothelin related peptides (SMRP) and osteopontin as protein biomarkers for malignant mesothelioma: analytical validation of ELISA based assays and characterization at mRNA and protein levels — A.J. Rai, R.M. Flores, et al. (2010)
• Factors affecting soluble mesothelin related protein levels in an asbestos-exposed population — E.K. Park, P.S. Thomas, et al. (2010)
• Serum soluble mesothelin-related protein (SMRP) and fibulin-3 levels correlate with baseline malignant pleural mesothelioma (MPM) tumor volumes but are not useful as biomarkers of response in an immunotherapy trial — S.I. Katz, L. Roshkovan, et al. (2021)
• Mesothelin (MSLN) methylation and soluble mesothelin-related protein levels in a Chinese asbestos-exposed population — M. Yu, Y. Zhang, et al. (2015)
• Mesothelin methylation, soluble mesothelin related protein levels and inflammation profiling in workers chronically exposed to naturally occurring asbestos fibers — C. Ledda, C. Loreto, et al. (2024)

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