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

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.

SUBMITTER: Goricar K

PROVIDER: S-EPMC7087423 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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

Goricar Katja K Kovac Viljem V Dodic-Fikfak Metoda M Dolzan Vita V Franko Alenka A

Radiology and oncology 20200307 1

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 ...[more]

PMID: 32187018

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Project description:BackgroundAsbestos exposure is associated with different asbestos-related diseases, including malignant mesothelioma (MM). MM diagnosis is confirmed with immunohistochemical analysis of several markers, including calretinin. Increased circulating calretinin was also observed in MM. The aim of the study was to determine if CALB2 polymorphisms or polymorphisms in genes that can regulate calretinin expression are associated with serum calretinin levels or MM susceptibility.Subjects and methodsThe study included 288 MM patients and 616 occupationally asbestos-exposed subjects without MM (153 with asbestosis, 380 with pleural plaques and 83 without asbestos-related disease). Subjects were genotyped for seven polymorphisms in CALB2, E2F2, MIR335, NRF1 and SEPTIN7 genes using competitive allele-specific polymerase chain reaction (PCR). Serum calretinin was determined with ELISA in 545 subjects. Nonparametric tests, logistic regression and receiver operating characteristic (ROC) curve analysis were used for statistical analysis.ResultsCarriers of at least one polymorphic CALB2 rs889704 allele had lower calretinin levels (P = 0.036). Carriers of two polymorphic MIR335 rs3807348 alleles had higher calretinin (P = 0.027), while carriers of at least one polymorphic NRF1 rs13241028 allele had lower calretinin levels (P = 0.034) in subjects without MM. Carriers of two polymorphic E2F2 rs2075995 alleles were less likely to develop MM (odds ratio [OR] = 0.64, 95% confidence interval [CI] = 0.43-0.96, P = 0.032), but the association was no longer significant after adjustment for age (P = 0.093). Optimal serum calretinin cut-off values differentiating MM patients from other subjects differed according to CALB2, NRF1, E2F2, and MIR335 genotypes.ConclusionsThe results of presented study suggest that genetic variability could influence serum calretinin levels. These findings could contribute to a better understanding of calretinin regulation and potentially to earlier MM diagnosis.

Project description:BackgroundDespite the available information on cancer risk, asbestos is used in large areas in the world, mostly in the production of asbestos cement. Moreover, questions are raised regarding the shape of the dose response relation, the relation with time since exposure and the association with neoplasms in various organs. We conducted a study on the relationship between cumulative asbestos exposure and mortality from asbestos related diseases in a large Italian pool of 21 cohorts of asbestos-cement workers with protracted exposure to both chrysotile and amphibole asbestos.MethodsThe cohort included 13,076 workers, 81.9% men and 18.1% women, working in 21 Italian asbestos-cement factories, with over 40?years of observation. Exposure was estimated by plant and period, and weighted for the type of asbestos used. Data were analysed with consideration of cause of death, cumulative exposure and time since first exposure (TSFE), and by gender. SMRs were computed using reference rates by region, gender and calendar time. Poisson regression models including cubic splines were used to analyse the effect of cumulative exposure to asbestos and TSFE on mortality for asbestos-related diseases. 95% Confidence Intervals (CI) were computed according to the Poisson distribution.ResultsMortality was significantly increased for 'All Causes' and 'All Malignant Neoplasm (MN)', in both genders. Considering asbestos related diseases (ARDs), statistically significant excesses were observed for MN of peritoneum (SMR: men 14.19; women 15.14), pleura (SMR: 22.35 and 48.10), lung (SMR: 1.67 and 1.67), ovary (in the highest exposure class SMR 2.45), and asbestosis (SMR: 507 and 1023). Mortality for ARDs, in particular pleural and peritoneal malignancies, lung cancer, ovarian cancer and asbestosis increased monotonically with cumulative exposure. Pleural MN mortality increased progressively in the first 40?years of TSFE, then reached a plateau, while peritoneal MN showed a continuous increase. The trend of lung cancer SMRs also showed a flattening after 40?years of TSFE. Attributable proportions for pleural, peritoneal, and lung MN were respectively 96, 93 and 40%.ConclusionsMortality for ARDs was associated with cumulative exposure to asbestos. Risk of death from pleural MN did not increase indefinitely with TSFE but eventually reached a plateau, consistently with reports from other recent studies.

Dataset Information

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

Publications

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

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