Related Experiment Video
Updated: May 30, 2026
Generation and Expansion of Primary, Malignant Pleural Mesothelioma Tumor Lines
Published on: April 21, 2022
The relationship between tumor MSLN methylation and serum mesothelin (SMRP) in mesothelioma
Heather H Nelson1, Lindsay M Almquist, Jessica L LaRocca
1Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, USA. hhnelson@umn.edu roduction
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.
Insights
Epigenetic changes in the MSLN gene promoter explain the low sensitivity of the soluble mesothelin-related peptide (SMRP) biomarker for malignant pleural mesothelioma (MPM) screening. Understanding this mechanism may lead to improved diagnostic biomarkers.
Area of Science:
- Oncology
- Epigenetics
- Biomarker Discovery
Background:
- Malignant pleural mesothelioma (MPM) has a poor prognosis, necessitating early detection through effective screening biomarkers.
- Serum-measured soluble mesothelin-related peptide (SMRP) shows high specificity but insufficient sensitivity for MPM screening.
Purpose of the Study:
- To investigate if epigenetic silencing of the MSLN gene promoter in tumors contributes to the poor sensitivity of SMRP.
- To identify potential epigenetic targets for improving MPM diagnostic accuracy.
Main Methods:
- Analysis of a case series of MPM patients from the International Mesothelioma Program.
- Identification and analysis of CpG methylation in the MSLN promoter region using bisulfite pyrosequencing.
- Comparison of MSLN promoter methylation levels between normal pleura and tumor tissues, and correlation with serum SMRP levels.
Main Results:
- MSLN promoter methylation was significantly higher in normal pleura compared to tumor tissue (P < 6.0x10-9).
- Tumors from SMRP-negative patients exhibited significantly higher MSLN promoter methylation than SMRP-positive tumors (P < 0.03).
- Epigenetic silencing of MSLN promoter methylation in a subset of tumors explains the low sensitivity of the SMRP assay.
Conclusions:
- MSLN promoter methylation patterns differ between normal pleura and MPM tumors.
- Retained MSLN promoter methylation in certain MPM tumors is a key factor limiting SMRP assay sensitivity.
- These findings may facilitate the development of novel biomarkers to enhance MPM screening efficacy.
