Proteome screening of pleural effusions identifies galectin 1 as a diagnostic biomarker and highlights several prognostic biomarkers for malignant mesothelioma

Our plain-English summary of Proteome screening of pleural effusions identifies galectin 1 as a diagnostic biomarker and highlights several prognostic biomarkers for malignant mesothelioma, by F. Mundt, H.J. Johansson, J. Forshed, et al (Molecular & Cellular Proteomics, 2014).

The study

• Authors: F. Mundt, H.J. Johansson, J. Forshed, S. Arslan, M. Metintas, K. Dobra, J. Lehtiö, A. Hjerpe
• Journal: Molecular & Cellular Proteomics
• Published: 2014;13(3):701-15
• Cited by: 36 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant mesothelioma is an aggressive asbestos-induced cancer, and affected patients have a median survival of approximately one year after diagnosis. It is often difficult to reach a conclusive diagnosis, and ancillary measurements of soluble biomarkers could increase diagnostic accuracy. Unfortunately, few soluble mesothelioma biomarkers are suitable for clinical application. Here we screened the effusion proteomes of mesothelioma and lung adenocarcinoma patients to identify novel soluble mesothelioma biomarkers. We performed quantitative mass-spectrometry-based proteomics using isobaric tags for quantification and used narrow-range immobilized pH gradient/high-resolution isoelectric focusing (pH 4-4.25) prior to analysis by means of nano liquid chromatography coupled to MS/MS. More than 1,300 proteins were identified in pleural effusions from patients with malignant mesothelioma (n = 6), lung adenocarcinoma (n = 6), or benign mesotheliosis (n = 7). Data are available via ProteomeXchange with identifier PXD000531. The identified proteins included a set of known mesothelioma markers and proteins that regulate hallmarks of cancer such as invasion, angiogenesis, and immune evasion, plus several new candidate proteins. Seven candidates (aldo-keto reductase 1B10, apolipoprotein C-I, galectin 1, myosin-VIIb, superoxide dismutase 2, tenascin C, and thrombospondin 1) were validated by enzyme-linked immunosorbent assays in a larger group of patients with mesothelioma (n = 37) or metastatic carcinomas (n = 25) and in effusions from patients with benign, reactive conditions (n = 16). Galectin 1 was identified as overexpressed in effusions from lung adenocarcinoma relative to mesothelioma and was validated as an excellent predictor for metastatic carcinomas against malignant mesothelioma. Galectin 1, aldo-keto reductase 1B10, and apolipoprotein C-I were all identified as potential prognostic biomarkers for malignant mesothelioma. This analysis of the effusion proteome furthers our understanding of malignant mesothelioma, identified galectin 1 as a potential diagnostic biomarker, and highlighted several possible prognostic biomarkers of this disease.

In plain English

This laboratory study looked for proteins in pleural effusions (fluid that collects around the lungs) that might help diagnose malignant mesothelioma or predict survival. In a discovery phase, the authors used mass spectrometry on effusions from six patients with epithelioid mesothelioma, six with lung adenocarcinoma and seven with benign pleurisy, and identified 1,371 proteins. Seven candidate proteins were then measured with ELISA tests in effusions from 37 mesothelioma patients, 25 patients with metastatic carcinomas and 16 patients with benign conditions, all collected in Eskisehir, Turkey. Galectin 1 levels were lower in mesothelioma than in metastatic carcinoma. Its area under the curve for distinguishing mesothelioma from metastatic carcinoma was 0.93 (95% confidence interval 0.86–0.99). Among mesothelioma patients, levels of galectin 1, aldo-keto reductase 1B10 and apolipoprotein C-I were associated with survival. The authors concluded that galectin 1 should be considered a prime candidate for clinical validation in mesothelioma diagnosis, and that the three survival-related proteins need future study. They noted the small number of samples and the need to test against other cancers, such as ovarian and gastrointestinal cancers.

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 study: mass-spectrometry proteomics screening of pleural effusions, followed by ELISA validation of selected proteins in a larger patient group, with diagnostic accuracy (ROC) and survival analyses
• Who was studied: Discovery group: pleural effusions from 6 patients with epithelioid mesothelioma, 6 with lung adenocarcinoma (all collected in Eskisehir, Turkey) and 7 with benign pleurisy/mesotheliosis (collected in Stockholm, Sweden). Validation group, all collected in Eskisehir, Turkey: 37 mesothelioma patients (30 epithelioid, 5 biphasic, 2 sarcomatoid), 25 with metastatic carcinomas (20 lung, 4 breast, 1 kidney), and 16 with benign conditions (9 benign asbestos pleuritis, 3 parapneumonic pleurisy, 2 tuberculosis, 2 congestive heart failure). Collection dates are not given.
• Exposure: Asbestos exposure was not the subject of measurement; no fiber types are reported. The authors state that the mesothelioma and lung adenocarcinoma patients in the discovery group had similar smoking habits and asbestos exposure, with a wide range in both groups. The benign validation group included 9 patients with benign asbestos pleuritis.
• Main results:
  • In the discovery screening, 1,371 proteins in total were identified in the pleural effusions.
  • Of the seven proteins validated by ELISA, only superoxide dismutase 2, aldo-keto reductase 1B10 and galectin 1 had areas under the curve significantly different from 0.5.
  • Galectin 1 area under the curve for mesothelioma versus all non-mesothelioma patients was 0.87 (95% CI 0.79–0.95). For mesothelioma versus metastatic carcinoma it was 0.93 (95% CI 0.86–0.99). Galectin 1 was lower in mesothelioma, acting as a negative predictor.
  • For the same patients, the reference markers taken from an earlier study had these areas under the curve for mesothelioma versus metastatic carcinoma: hyaluronan 0.82 (0.70–0.94) and N-ERC/mesothelin 0.87 (0.77–0.96).
  • Mesothelioma patients with aldo-keto reductase 1B10 below 0.65 ng/ml had a median survival of 11 months, compared with 5.5 months for those above. The hazard ratio was 3.4 (95% CI 1.33–8.63).
  • Mesothelioma patients with high apolipoprotein C-I had a mean survival of 10 months, compared with 4.5 months for low expressers. The reciprocal hazard ratio was 2.30 (1.4–9.0).
  • At a cutoff of 22.5 ng/ml, mesothelioma patients with high galectin 1 had a median survival of 4.5 months, compared with 9.5 months for low expressers. The hazard ratio was 2.34 (1.02–5.41).
• The authors' conclusion: The authors concluded that galectin 1 is a negative predictor of malignant mesothelioma. They considered its discriminating ability equal to or greater than that of N-ERC/mesothelin and hyaluronan, and said it should be considered a prime candidate for clinical validation. They described aldo-keto reductase 1B10, apolipoprotein C-I and galectin 1 as prognostic candidates needing future study.
• Limitations the authors state:
  • The discovery groups were small and varied between patients, so many protein differences had high false discovery rates (q-values).
  • The candidates still need to be tested against a broader range of cancers, such as ovarian and gastrointestinal cancers.
  • Galectin 1 must be validated in a larger cohort of patients.
  • The authors suggest that the lack of diagnostic value for apolipoprotein C-I, compared with an earlier study, might reflect the validation method or the particular ELISA used.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma, Pleural plaques and thickening.

Medical terms in this study, explained in our Lexicon: Pleural Effusion, Biomarker, Malignant Mesothelioma, Median Survival, Mesothelioma, Lung Adenocarcinoma, Angiogenesis, Superoxide.

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