Mesothelin promoter variants are associated with increased soluble mesothelin-related peptide levels in asbestos-exposed individuals.
Soluble mesothelin-related peptide (SMRP) is a promising diagnostic biomarker for malignant pleural mesothelioma (MPM), but various confounders hinder its usefulness in surveillance programmes. We previously showed that a single nucleotide polymorphism (SNP) within the 3'untranslated region (3'UTR) of themesothelin(MSLN) gene could affect the levels of SMRP.



To focus on SNPs located withinMSLNpromoter as possible critical genetic variables in determining SMRP levels.



The association between SMRP and SNPs was tested in 689 non-MPM subjects and 70 patients with MPM. Reporter plasmids carrying the four most common haplotypes were compared in a dual luciferase assay, and in silico analyses were performed to investigate the putative biological role of the SNPs.



We found a strong association between serum SMRP and variant alleles of rs3764247, rs3764246 (in strong linkage disequilibrium with rs2235504) and rs2235503 in non-MPM subjects. Inclusion of the genotype information led to an increase in SMRP specificity from 79.9% to 85.5%. Although not statistically significant, the group with MPM showed the same trend of association. According to the in vitro luciferase study, rs3764247 itself had a functional role. In silico approaches showed that the binding sites for transcription factors such as Staf and ZNF143 could be affected by this SNP. The other SNPs were shown to interact with each other in a more complex way.



These data support the suggestion that SMRP performance is affected by individual (ie, genetic) variables and thatMSLNexpression is influenced by SNPs located within the promoter regulatory region.
Department of Biology, University of Pisa, Via Derna 1, Pisa, Italy.
Chiara
C
De Santi
Department of Biology, University of Pisa, Via Derna 1, Pisa, Italy.
Perla
P
Pucci
Preventive and Occupational Medicine, University Hospital of Pisa, Pisa, Italy.
Alessandra
A
Bonotti
Department of Biology, University of Pisa, Via Derna 1, Pisa, Italy.
Ombretta
O
Melaiu
Department of Biology, University of Pisa, Via Derna 1, Pisa, Italy.
Monica
M
Cipollini
Department of Biology, University of Pisa, Via Derna 1, Pisa, Italy.
Roberto
R
Silvestri
Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Praha, Czech Republic.
Veronika
V
Vymetalkova
Department of Biology, University of Pisa, Via Derna 1, Pisa, Italy.
Elisa
0000-0002-5444-354X
E
Barone
Department of Biology, University of Pisa, Via Derna 1, Pisa, Italy.
Elisa
E
Paolicchi
Department of Biology, University of Pisa, Via Derna 1, Pisa, Italy.
Alda
A
Corrado
Department of Biology, University of Pisa, Via Derna 1, Pisa, Italy.
Irene
I
Lepori
Department of Biology, University of Pisa, Via Derna 1, Pisa, Italy.
Irene
I
Dell'Anno
Department of Biology, University of Pisa, Via Derna 1, Pisa, Italy.
Lucia
L
Pellè
Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Praha, Czech Republic.
Pavel
P
Vodicka
School of Environment and Life Sciences, University of Salford, Manchester, United Kingdom.
Luciano
L
Mutti
Department of Translational Research and of new Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
Rudy
R
Foddis
Department of Translational Research and of new Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.
Alfonso
A
Cristaudo
Department of Biology, University of Pisa, Via Derna 1, Pisa, Italy.
Federica
F
Gemignani
Department of Biology, University of Pisa, Via Derna 1, Pisa, Italy.
Stefano
S
Landi
D000368:Aged; D000483:Alleles; D000704:Analysis of Variance; D001194:Asbestos / Q000009:adverse effects; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics*; D005260:Female; D058851:GPI-Linked Proteins / Q000097:blood* / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007558:Italy; D008156:Luciferases; D008175:Lung Neoplasms / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D000090204:Mesothelin; D008654:Mesothelioma / Q000097:blood / Q000175:diagnosis* / Q000235:genetics*; D000086002:Mesothelioma, Malignant; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012680:Sensitivity and Specificity
D014408:Biomarkers, Tumor; D058851:GPI-Linked Proteins; C000715527:MSLN protein, human; D001194:Asbestos; D008156:Luciferases; D000090204:Mesothelin
health surveillance; mesothelioma; polymorphisms