Identification of a seven glycopeptide signature for malignant pleural mesothelioma in human serum by selected reaction monitoring

Our plain-English summary of Identification of a seven glycopeptide signature for malignant pleural mesothelioma in human serum by selected reaction monitoring, by F. Cerciello, M. Choi, A. Nicastri, et al (Clinical Proteomics, 2013).

The study

• Authors: F. Cerciello, M. Choi, A. Nicastri, D. Bausch-Fluck, A. Ziegler, O. Vitek, E. Felley-Bosco, R. Stahel, R. Aebersold, B. Wollscheid
• Journal: Clinical Proteomics
• Published: 2013;10(1):16
• Cited by: 38 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Serum biomarkers can improve diagnosis and treatment of malignant pleural mesothelioma (MPM). However, the evaluation of potential new serum biomarker candidates is hampered by a lack of assay technologies for their clinical evaluation. Here we followed a hypothesis-driven targeted proteomics strategy for the identification and clinical evaluation of MPM candidate biomarkers in serum of patient cohorts.

Results: Based on the hypothesis that cell surface exposed glycoproteins are prone to be released from tumor-cells to the circulatory system, we screened the surfaceome of model cell lines for potential MPM candidate biomarkers. Selected Reaction Monitoring (SRM) assay technology allowed for the direct evaluation of the newly identified candidates in serum. Our evaluation of 51 candidate biomarkers in the context of a training and an independent validation set revealed a reproducible glycopeptide signature of MPM in serum which complemented the MPM biomarker mesothelin.

Conclusions: Our study shows that SRM assay technology enables the direct clinical evaluation of protein-derived candidate biomarker panels for which clinically reliable ELISA's currently do not exist.

In plain English

This laboratory study searched for blood markers of malignant pleural mesothelioma (MPM). The authors chose candidate protein fragments (glycopeptides) from cell-line surface proteins, and 51 of 112 were detected in serum by mass spectrometry. Training on 25 MPM patients, 25 healthy donors and 25 non-small cell lung cancer patients, they built a six-glycopeptide panel. It separated MPM from healthy donors with an area under the curve (AUC) of 0.94 (95% confidence interval 0.87 to 0.99), and 0.94 (0.86 to 0.99) in validation (30 MPM, 29 healthy donors). Against 28 lung cancer patients in validation it failed (AUC 0.56, 0.40 to 0.71). Adding the known marker mesothelin gave a seven-glycopeptide signature. In a sub-validation group, it scored 0.95 (0.83 to 1.0) comparing 11 MPM patients with 12 healthy donors, and 0.84 (0.66 to 0.97) comparing them with 12 lung cancer patients. A mesothelin blood test (ELISA) scored 0.93 (0.84 to 1.0) and 0.80 (0.59 to 0.95) in the same subjects. The authors noted most patients had advanced disease and controls lacked other non-cancerous lung conditions, so accuracy could be lower in broader populations.

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: Biomarker discovery and evaluation study: surface-protein screening of cell lines, then targeted mass spectrometry (selected reaction monitoring) of patient and control serum, with training and validation sets
• Who was studied: Serum from untreated patients with MPM or non-small cell lung cancer (NSCLC) and from healthy blood donors. The training set had 25 MPM, 25 healthy donors and 25 NSCLC. The validation set had 30 MPM, 29 healthy donors and 28 NSCLC. A mesothelin comparison used 75 subjects (23 MPM, 26 healthy donors, 26 NSCLC). Cell lines included four MPM, two lung adenocarcinoma and two non-cancerous pleural lines. Collection dates were not given.
• Exposure: Asbestos exposure was not studied. The article measured serum glycopeptide levels as possible markers of MPM.
• Main results:
  • Of 112 surface-derived candidate glycopeptides tested, 51 were detected in serum.
  • In the training set, the six-glycopeptide panel distinguished MPM from healthy donors with an AUC of 0.94 (95% CI 0.87 to 0.99).
  • In the validation set (30 MPM, 29 healthy donors, 28 NSCLC), the panel distinguished MPM from healthy donors with an AUC of 0.94 (95% CI 0.86 to 0.99).
  • The six-glycopeptide panel failed to distinguish MPM from NSCLC. Its AUC was 0.77 (95% CI 0.62 to 0.91) in the training set and 0.56 (95% CI 0.40 to 0.71) in the validation set.
  • In the 75 subjects with ELISA data, mesothelin ELISA distinguished MPM from NSCLC with an AUC of 0.84 (95% CI 0.71 to 0.94), better than the six-glycopeptide panel (AUC 0.54).
  • In a sub-validation set of 11 MPM, 12 healthy donors and 12 NSCLC, the seven-glycopeptide signature (including mesothelin) distinguished MPM from healthy donors with an AUC of 0.95 (95% CI 0.83 to 1.0) and accuracy of 91%. It distinguished MPM from NSCLC with an AUC of 0.84 (95% CI 0.66 to 0.97).
  • In the same sub-validation subjects, mesothelin ELISA had an AUC of 0.93 (95% CI 0.84 to 1.0) for MPM versus healthy donors.
  • In the same sub-validation subjects, mesothelin ELISA had an AUC of 0.80 (95% CI 0.59 to 0.95) and accuracy of 74% for MPM versus NSCLC.
• The authors' conclusion: The authors concluded that the targeted mass-spectrometry approach produced a seven-glycopeptide signature with diagnostic potential for MPM. They also concluded that the method is suited to fast clinical evaluation of candidate serum markers.
• Limitations the authors state:
  • Most patients had advanced disease, and controls did not include people with chronic inflammation or other non-cancerous lung diseases.
  • Accuracy of the signature could be lower in more varied populations.
  • The study cannot say whether the markers are specific to MPM or more generally linked to cancer.
  • Including hypoxia up-regulated protein 1, a heat shock protein, raised a possible concern about specificity.

Topics

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Biomarker, Glycoprotein, Mesothelin.

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