Two novel polymorphisms in 5' flanking region of the mesothelin gene are associated with soluble mesothelin-related peptide (SMRP) levels

Our plain-English summary of Two novel polymorphisms in 5' flanking region of the mesothelin gene are associated with soluble mesothelin-related peptide (SMRP) levels, by A. Cristaudo, R. Foddis, A. Bonotti, et al (The International Journal of Biological Markers, 2011).

The study

• Authors: A. Cristaudo, R. Foddis, A. Bonotti, S. Simonini, A. Vivaldi, G. Guglielmi, R. Bruno, F. Gemignani, S. Landi
• Journal: The International Journal of Biological Markers
• Published: 2011;26(2):117-23
• Cited by: 13 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Background And Aims: Increased concentrations of soluble mesothelin-related peptides (SMRP) have been found in sera of patients with malignant pleural mesothelioma (MPM) even if a relatively high rate of false positives has hampered their clinical use as a tumor marker. Individual SMRP levels could be affected by polymorphic elements. The aim of this study was to investigate the association between single nucleotide polymorphisms within the promoter-5'UTR regions and SMRP levels in healthy asbestos-exposed individuals and patients suffering from MPM.?

Methods: The promoter-5'UTR regions of the mesothelin gene were genotyped in 59 healthy asbestos-exposed subjects and 27 MPM patients. SMRP levels were measured using a commercially available ELISA kit.?

Results: Two novel polymorphisms, an A>C variant (called New1) and a C>T variant (called New2), were identified. In healthy subjects, high SMRP levels were associated with the C-variant of New1, with an average 1.62-fold increase compared with AA homozygotes (p<0.0001). Most of the C-allele carriers had SMRP levels above the threshold of 1.00 nM. We set two different SMRP cutoffs on the basis of the combined New1+New2 genotypes.?

Conclusions: New1-New2 genotypes could be employed as markers for setting individualized and appropriate thresholds of "normality" when SMRP is used in surveillance programs of asbestos-exposed people.

In plain English

This genetic study from the University of Pisa, Italy, asked whether small DNA differences near the start of the mesothelin gene are linked to blood levels of soluble mesothelin-related peptide (SMRP), a proposed marker for malignant pleural mesothelioma. The authors sequenced this gene region in 59 healthy Caucasian men with past occupational asbestos exposure and 27 patients with epithelial-type malignant pleural mesothelioma. They found two previously unreported variants, which they called New1 and New2. Among the healthy men, carriers of the C variant of New1 had average SMRP levels 1.62 times higher than men with the AA form (p less than 0.0001). Of the 25 carriers, 17 had levels above 1 nM, compared with 4 of 34 AA men. Among the patients, the New1 difference was not statistically significant. The authors set a cutoff of 1.76 nM for variant carriers and 1 nM for everyone else. With these cutoffs, telling healthy subjects from patients had a sensitivity of 55.6% and a specificity of 91.5%. A single 1 nM cutoff gave 70.4% and 64.4%. The authors concluded that these genotypes could help set individual SMRP thresholds in surveillance. They planned to confirm this in a larger group.

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 DNA variants in the mesothelin gene promoter-5' region with serum SMRP levels
• Who was studied: 59 healthy, unrelated Caucasian men (mean age 56) previously exposed to asbestos at work, from the Tyrrhenian coast of Italy and recruited through an occupational surveillance program at the University of Pisa Hospital, plus 27 patients with epithelial-type malignant pleural mesothelioma (mean age 69). People with pleural plaques or respiratory diseases were excluded from the healthy group.
• Exposure: Occupational asbestos exposure, fiber type not specified. Mean duration was 17.6 years (range 11-29) in the healthy subjects and 22.6 years (range 6-41) in the mesothelioma patients. The main factor studied was genotype at mesothelin gene variants, not the level of exposure.
• Main results:
  • Two previously unreported variants were found: New1 (A to C) at position -2642 and New2 (C to T) at position -2641 from the translation start site.
  • In healthy asbestos-exposed subjects, carriers of the New1 C allele had average SMRP levels 1.62-fold higher than AA homozygotes (p less than 0.0001).
  • In healthy subjects, most New1 C-allele carriers had SMRP above 1.00 nM. Table IV shows 17 of 25 carriers (AC+CC) above 1 nM, compared with 4 of 34 AA homozygotes.
  • In healthy subjects, the New2 variant was only marginally associated with higher SMRP (p=0.085).
  • In healthy subjects, those carrying a variant at New1 or New2 (group 1, n=29) had mean SMRP 1.17 nM. Those with neither variant (group 0, n=30) had 0.635 nM (p less than 0.0001).
  • In the mesothelioma patients, New1 C-allele carriers did not differ significantly in SMRP from AA homozygotes (p=0.247). No New2 carriers were found among the patients.
  • Based on ROC curves, the best SMRP cutoff was 1 nM for non-carriers and 1.76 nM for variant carriers.
  • Using genotype-specific cutoffs to separate healthy subjects from mesothelioma patients gave a sensitivity of 55.6% and a specificity of 91.5%. A single 1 nM cutoff gave a sensitivity of 70.4% and a specificity of 64.4%.
  • New1 was only weakly linked (r2 of 0.23) to a variant in another part of the gene (rs1057147) that the authors had previously tied to high SMRP. The authors suggested the two regions may affect SMRP independently.
• The authors' conclusion: The authors concluded that New1-New2 genotypes could be used to set individualized thresholds of normal SMRP when SMRP is used to monitor asbestos-exposed people.
• Limitations the authors state:
  • The authors did not identify the proteins that regulate the gene and did not test how each variant form works in the cell.
  • The authors stated that the two cutoffs still need to be confirmed in a larger population.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelin, Soluble Mesothelin-Related Peptides (SMRP), Pleural Mesothelioma, Tumor Marker.

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)
• Polymorphisms in the putative micro-RNA-binding sites of mesothelin gene are associated with serum levels of mesothelin-related protein — A. Cristaudo, R. Foddis, et al. (2010)
• A common polymorphism within MSLN affects miR-611 binding site and soluble mesothelin levels in healthy people — S. Garritano, C. De Santi, et al. (2014)
• 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)
• Soluble mesothelin-related peptides levels in patients with malignant mesothelioma — A. Franko, V. Dolzan, et al. (2012)
• Association of MiR-126 with soluble mesothelin-related peptides, a marker for malignant mesothelioma — L. Santarelli, E. Strafella, et al. (2011)

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