title: The relationship between tumor MSLN methylation and serum mesothelin (SMRP) in mesothelioma.
abstract: Malignant pleural mesothelioma (MPM) remains a cancer of poor prognosis. It is hoped that implementation of effective screening biomarkers will lead to earlier diagnoses and improved outcomes. Serum-measured soluble mesothelin-related peptide (SMRP) has been demonstrated to have excellent specificity for MPM, but poor sensitivity precludes its use as a screening biomarker. Using a case series of MPM patients from the International Mesothelioma Program at the Brigham and Women's hospital, we sought to determine whether epigenetic change at the MSLN gene in patient tumors is responsible for the poor sensitivity of SMRP. We identified three potential target regions for CpG methylation silencing in the MSLN promoter, one of which was amenable to bisulfite pyrosequencing and located 214 bp upstream of the transcription start site. MSLN promoter methylation was significantly higher in normal pleura than tumor tissue (P < 6.0x10-9). Next, we compared cases according to serum SMRP status and observed that MSLN methylation was significantly higher among tumors from patients testing negative for SMRP (< 1.5nM) versus those that were SMRP positive (P < 0.03). These results demonstrate that MSLN is normally methylated in the pleura, and that methylation is lost in most tumors. However, in a subset of tumors methylation is retained, and this mechanism explains the poor sensitivity of the SMRP assay. These results may lead to additional biomarker targets that will resolve the poor sensitivity of the SMRP assay and allow implementation of screening among exposed populations.
authors.affiliation: Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, USA. hhnelson@umn.edu roduction
authors.forename: Heather H
authors.initials: HH
authors.lastname: Nelson
authors.forename: Lindsay M
authors.initials: LM
authors.lastname: Almquist
authors.forename: Jessica L
authors.initials: JL
authors.lastname: LaRocca
authors.forename: Silvia L
authors.initials: SL
authors.lastname: Plaza
authors.forename: Geralyn M
authors.initials: GM
authors.lastname: Lambert-Messerlian
authors.forename: David J
authors.initials: DJ
authors.lastname: Sugarbaker
authors.forename: Raphael
authors.initials: R
authors.lastname: Bueno
authors.forename: John J
authors.initials: JJ
authors.lastname: Godleski
authors.forename: Carmen J
authors.initials: CJ
authors.lastname: Marsit
authors.forename: Brock C
authors.initials: BC
authors.lastname: Christensen
authors.forename: Karl T
authors.initials: KT
authors.lastname: Kelsey
mesh_terms: D000368:Aged; D001195:Asbestosis / Q000097:blood; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D058851:GPI-Linked Proteins / Q000097:blood* / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D000090204:Mesothelin; D008654:Mesothelioma / Q000097:blood* / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D010997:Pleural Neoplasms / Q000097:blood* / Q000235:genetics* / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D058851:GPI-Linked Proteins; C000715527:MSLN protein, human; D000090204:Mesothelin