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

Our plain-English summary of Evaluation of soluble mesothelin-related peptides and MSLN genetic variability in asbestos-related diseases, by K. Goricar, V. Kovac, M. Dodic-Fikfak, et al (Radiology and Oncology, 2020).

The study

• Authors: K. Goricar, V. Kovac, M. Dodic-Fikfak, V. Dolzan, A. Franko
• Journal: Radiology and Oncology
• Published: 2020;54(1):86-95
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background Asbestos 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 methods Among 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. Results MM 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). Conclusions MSLN 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.

In plain English

This Slovenian study looked at a blood marker called soluble mesothelin-related peptides (SMRP) and a common variant, rs1057147, in the mesothelin gene (MSLN). It included 782 people: 154 patients with malignant mesothelioma (MM) and 628 occupationally asbestos-exposed people with pleural plaques (410), asbestosis (149) or no asbestos-related disease (69). SMRP was measured in only 86 of the MM patients. Their median SMRP was 2.43 nmol/l, compared with 0.13 nmol/l in all other subjects. In people without MM, carriers of the variant had higher SMRP levels. In MM patients the difference was not statistically significant. The variant was not associated with the odds of having MM. The best SMRP cutoff differed by genotype. MM patients carrying at least one variant copy had shorter median overall survival (15.1 vs 22.2 months; HR 1.72, 95% CI 1.15–2.55). SMRP level alone was not significantly linked to survival. The authors concluded that MSLN variation affects SMRP levels. They noted limitations including missing serum samples and no data on body mass index or kidney function.

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: Comparison of a blood biomarker (serum SMRP) and a gene variant (MSLN rs1057147) across groups of asbestos-exposed people and patients with asbestos-related diseases, with survival analysis in the mesothelioma patients
• Who was studied: 782 subjects in Slovenia. 154 had malignant mesothelioma (138 pleural, 16 peritoneal), treated at the Institute of Oncology Ljubljana between 1 January 2004 and 31 December 2012. 628 were occupationally asbestos-exposed people who presented at the State Board for the Recognition of Occupational Asbestos Diseases between 1 January 1998 and 31 December 2007: 69 with no asbestos-related disease, 410 with pleural plaques and 149 with asbestosis.
• Exposure: The non-mesothelioma groups were occupationally exposed to asbestos. No fiber types, products, jobs or doses are described. The factors analyzed were serum SMRP level and MSLN rs1057147 genotype.
• Main results:
  • SMRP levels: the 86 MM patients with serum at diagnosis had a median of 2.43 (0.44–8.62) nmol/l. All other subjects had a median of 0.13 (0.00–0.55) nmol/l (p less than 0.001).
  • Telling MM patients apart from all other subjects: the manufacturer's cutoff of 1.5 nmol/l gave 93% specificity and 59.3% sensitivity. The cutoff with the best combined performance, 1.11 nmol/l, gave 88.5% specificity and 65.1% sensitivity.
  • The MSLN rs1057147 variant was not associated with the odds of having MM. For carriers of one or two variant copies (GA plus AA) compared with GG, the odds ratio was 1.28 (95% CI 0.90–1.82, p = 0.174).
  • SMRP differed significantly by genotype in subjects with no disease, in subjects with pleural plaques, and in all non-MM subjects combined (all p less than 0.001). In all 612 non-MM subjects combined, median SMRP was 0.07 nmol/l for GG, 0.33 for GA and 0.33 for AA. The difference was not significant in asbestosis patients (p = 0.055) or MM patients (p = 0.424).
  • When MM patients were compared with non-MM subjects of one genotype at a time, the cutoff with the best combined sensitivity and specificity differed by genotype. It was 0.87 nmol/l for GG (specificity 0.911) and 1.68 nmol/l for AA (specificity 0.927).
  • In 10 peritoneal MM patients, SMRP was significantly higher than in pleural MM patients (median 8.72 vs 1.78 nmol/l, p = 0.011).
  • In MM patients, those carrying at least one variant allele had shorter median overall survival than those with two wild-type alleles: 15.1 vs 22.2 months (HR = 1.72, 95% CI 1.15–2.55, p = 0.008).
  • Progression-free survival was shorter in variant carriers, but not significantly (HR = 1.39, 95% CI 0.98–1.98, p = 0.068).
  • In MM patients, SMRP level at diagnosis was not significantly associated with progression-free survival (HR = 0.99, p = 0.574) or overall survival (HR = 1.03, 95% CI 0.99–1.06, p = 0.110).
  • In a model including both SMRP at diagnosis and the variant, the variant was the strongest predictor of overall survival (HR = 2.65, 95% CI 1.41–4.99, p = 0.002).
• The authors' conclusion: The authors concluded that MSLN genetic variability affects serum SMRP levels and could help define better SMRP cutoff values for MM diagnosis and screening. They also concluded that it may influence the survival of MM patients, and that combining genetic and serum data could serve as a better biomarker.
• Limitations the authors state:
  • Other variants in the MSLN 5' UTR region, which could also affect SMRP levels, were not studied.
  • Serum samples at diagnosis were available for only 86 of the 154 MM patients. The authors did not believe this introduced systematic bias, but these patients were older and had worse performance status.
  • No data were available on body mass index or kidney function, which some studies suggest may affect SMRP levels.

Topics

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

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

Related studies

• Soluble mesothelin-related peptides levels in patients with malignant mesothelioma — A. Franko, V. Dolzan, et al. (2012)
• Evaluation of soluble mesothelin-related peptide as a diagnostic marker of malignant pleural mesothelioma effusions: its contribution to cytology — P.A. Canessa, M.C. Franceschini, et al. (2013)
• 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 to Monitor Recurrence After Resection of Pleural Mesothelioma — B.M. Burt, H.S. Lee, et al. (2017)
• Two novel polymorphisms in 5' flanking region of the mesothelin gene are associated with soluble mesothelin-related peptide (SMRP) levels — A. Cristaudo, R. Foddis, et al. (2011)
• Serum levels of soluble mesothelin-related peptides in malignant and nonmalignant asbestos-related pleural disease: relation with past asbestos exposure — J.A. Rodríguez Portal, E. Rodríguez Becerra, et al. (2009)

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