The relationship between tumor MSLN methylation and serum mesothelin (SMRP) in mesothelioma

Heather H. Nelson, Lindsay M. Almquist, Jessica L. LaRocca, Silvia L. Plaza, Geralyn Lambert-Messerlian, David J. Sugarbaker, Raphael Bueno, John J. Godleski, Carmen J. Marsit, Brock C. Christensen, Karl T. Kelsey

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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 < 6.0 x 10-9). 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 (<1.5 nM) 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.

Original languageEnglish (US)
Pages (from-to)1029-1034
Number of pages6
JournalEpigenetics
Volume6
Issue number8
DOIs
StatePublished - Aug 2011

Bibliographical note

Funding Information:
facturer’s protocol (Qiagen). DNA was modified by sodium This work was supported by the International Mesothelioma bisulfite to convert unmethylated cytosines to uracil using the Program at Brigham and Women’s Hospital and NIH grants EZ DNA Methylation kit (Zymo Research) according to the R01CA126939, R01CA078609, P30 CA077598.

Keywords

  • MSLN
  • Mesothelioma
  • Methylation
  • SMRP
  • Screening

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