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

Our plain-English summary of The relationship between tumor MSLN methylation and serum mesothelin (SMRP) in mesothelioma, by H.H. Nelson, L.M. Almquist, J.L. LaRocca, et al (Epigenetics, 2011).

The study

• Authors: H.H. Nelson, L.M. Almquist, J.L. LaRocca, S.L. Plaza, G.M. Lambert-Messerlian, D.J. Sugarbaker, R. Bueno, J.J. Godleski, C.J. Marsit, B.C. Christensen, K.T. Kelsey
• Journal: Epigenetics
• Published: 2011;6(8):1029-34
• Cited by: 24 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This study asked why a blood test for malignant pleural mesothelioma, serum soluble mesothelin-related peptide (SMRP), misses many cases. The authors studied 179 mesothelioma patients from the International Mesothelioma Program at Brigham and Women's Hospital, 139 of whom reported asbestos exposure, and 18 disease-free controls. At the recommended cutoff of 1.5 nM, SMRP was 94.4% specific and 52.5% sensitive. The authors measured methylation, a chemical change that can switch genes off, in a region of the mesothelin (MSLN) gene. Average methylation was 67.9% in ten normal pleura samples and 21.4% in the 36 patient tumors available. Among tumors, it averaged 14.3% in SMRP-positive patients and 23.3% in SMRP-negative patients (p less than 0.03). Methylation patterns from the group's earlier work were also associated with SMRP levels. The authors concluded their study identified the likely cause of the test's poor sensitivity. They noted they had not shown a direct link between MSLN methylation and gene expression, the results were not completely concordant, they used few controls, and not all patients had tumor tissue.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Case series of mesothelioma patients with laboratory measurement of serum SMRP and tumor MSLN gene methylation, compared with non-diseased controls and normal pleura
• Who was studied: 179 incident malignant pleural mesothelioma cases from the International Mesothelioma Program at Brigham and Women's Hospital (Boston), identified beginning in 2005, plus 18 disease-free serum controls. Methylation was measured in 36 case tumors and 10 pathologically normal pleura samples from patients without mesothelioma.
• Exposure: The main factor studied was methylation of the MSLN (mesothelin) gene promoter in tumors. Patients' history of asbestos exposure was assessed by questionnaire or interview: Table 1 lists 139 cases (77.3%) as exposed and 40 (22.3%) as not exposed. No fiber types are named.
• Main results:
  • Using the 1.5 nM cutoff, serum SMRP was 94.4% specific and 52.5% sensitive for malignant pleural mesothelioma. Median SMRP was 1.71 nM in cases and 0.56 nM in non-diseased controls.
  • Average MSLN methylation was 67.9% in ten normal pleura samples and 21.4% in the 36 case tumors (p less than 6.0 x 10 to the power of minus 9).
  • Average tumor MSLN methylation was 14.3% among SMRP-positive patients and 23.3% among SMRP-negative patients (p less than 0.03).
  • Tumor methylation classes from the group's earlier study were significantly associated with serum SMRP (permutation p less than 0.0001), with higher SMRP in classes 5 and 7.
• The authors' conclusion: The authors concluded that MSLN is normally methylated in the pleura, that methylation is lost in most tumors but kept in some, and that their study identified the likely cause of SMRP's poor sensitivity, which could inform future biomarker development.
• Limitations the authors state:
  • The authors did not show a direct relationship between MSLN methylation and gene expression.
  • Methylation and SMRP results were not completely concordant, possibly because the measured CpG sites were not the ones most closely tied to MSLN expression.
  • Only a small number of controls was included.
  • Not all patients had tumor tissue available for study.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Mesothelin, Soluble Mesothelin-Related Peptides (SMRP), Mesothelioma, Pleural Mesothelioma, Prognosis, Biomarker, International Mesothelioma Program, Brigham and Women's Hospital.

Related studies

• Mesothelin (MSLN) promoter is hypomethylated in malignant mesothelioma, but its expression is not associated with methylation status of the promoter — K. Tan, K. Kajino, et al. (2010)
• Comparison of the diagnostic accuracy of the MSLN gene products, mesothelin and megakaryocyte potentiating factor, as biomarkers for mesothelioma in pleural effusions and serum — J. Creaney, S. Sneddon, et al. (2013)
• Mesothelin (MSLN) methylation and soluble mesothelin-related protein levels in a Chinese asbestos-exposed population — M. Yu, Y. Zhang, et al. (2015)
• Serum soluble mesothelin concentrations in malignant pleural mesothelioma: relationship to tumor volume, clinical stage and changes in tumor burden — J. Creaney, R.J. Francis, et al. (2011)
• Two novel polymorphisms in 5' flanking region of the mesothelin gene are associated with soluble mesothelin-related peptide (SMRP) levels — A. Cristaudo, R. Foddis, et al. (2011)
• Serum soluble mesothelin-related protein (SMRP) and fibulin-3 levels correlate with baseline malignant pleural mesothelioma (MPM) tumor volumes but are not useful as biomarkers of response in an immunotherapy trial — S.I. Katz, L. Roshkovan, et al. (2021)

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