Big and Free Fractions of Gamma-Glutamyltransferase: New Diagnostic Biomarkers for Malignant Mesothelioma?

Our plain-English summary of Big and Free Fractions of Gamma-Glutamyltransferase: New Diagnostic Biomarkers for Malignant Mesothelioma?, by R. Foddis, M. Franzini, A. Bonotti, et al (Diagnostics, 2022).

The study

• Authors: R. Foddis, M. Franzini, A. Bonotti, R. Marino, R. Silvestri, P. Fallahi, D. Chiappino, M. Emdin, A. Paolicchi, A. Cristaudo
• Journal: Diagnostics
• Published: 2022;12(2)
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a cancer mainly caused by asbestos fiber inhalation, characterized by an extremely long latency and poor prognosis. Recently, researchers have focused on testing the diagnostic ability of several biomarkers. Gamma-Glutamyltransferase (GGT) has been demonstrated to be the sum of several GGT sub-fractions activity, classified based on their molecular weight in big-GGT, medium-GGT, small-GGT, and free-GGT. This work aims to evaluate whether specific GGT fractional enzymatic activity patterns could be helpful in MPM diagnosis. We analyzed blood samples from 175 workers previously exposed to asbestos, 157 non-exposed healthy subjects, and 37 MPM patients through a molecular exclusion chromatographic method. We found a specific profile of GGT fractions activity, significantly associated with MPM, resulting in an increase in b-, m- activity, along with an evident, yet not significant, decrease in f-activity. Receiver-operating characteristic (ROC) analysis showed that the best Area Under Curve (AUC) value resulted from the combined index b/f (0.679, 95% CI: 0.582-0.777). Combining the b-/f-GGT activity with the levels of serum mesothelin-related protein (SMRP; another promising MPM biomarker) improved the diagnostic accuracy, increasing the AUC value to 0.875 (95% CI: 0.807-0.943, p = <0.0001). Since MPM has a specific pattern of GGT enzymatic activity, we could hypothesize that GGT fractions play different specific biochemical roles. The improvement in the diagnostic power given by the combination of these two biomarkers confirms that the strategy of biomarkers combination might be a better approach for MPM diagnosis.

In plain English

This Italian study tested whether forms ("fractions") of a blood enzyme, gamma-glutamyltransferase (GGT), could help diagnose malignant pleural mesothelioma. It measured them in 37 male patients with epithelioid mesothelioma, 175 previously asbestos-exposed workers and 157 unexposed healthy people from Pisa, recruited 2010 to 2015. Mesothelioma patients had higher "big" and "medium" fraction activity than both other groups. Their median "free" fraction (11.06 U/L) was close to the exposed workers' (11.04) and below the unexposed people's (11.84). None of these free-fraction differences was statistically significant. Exposed workers also had higher big and medium fractions than unexposed people. The big-to-free GGT ratio scored 0.679 on area under the curve, a measure of how well a test separates groups (95% confidence interval 0.582 to 0.777). Combined with another blood marker, SMRP, it reached 0.875 (interval 0.807 to 0.943) for separating patients from exposed workers. At the authors' best cut-off of 0.10, sensitivity was 87.50% and specificity 72.19%. The authors judged this accuracy still too low for clinical use but supported further research on GGT fractions. They noted the small number of mesothelioma cases.

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: Diagnostic biomarker study comparing blood measurements in mesothelioma patients with two comparison groups: previously asbestos-exposed workers and non-exposed healthy subjects, matched for gender, age and total GGT activity
• Who was studied: Recruited January 2010 to December 2015 at the University Hospital of Pisa, Italy. The study included 37 consecutive malignant pleural mesothelioma patients, all male and all epithelioid subtype, sampled before treatment. It also included 175 previously asbestos-exposed workers from a cancer screening cohort: 70 with benign respiratory diseases, 62 healthy-exposed and 43 with pleural plaques or unspecific lung nodules. The third group was 157 healthy non-exposed subjects from the MEHLP Study.
• Exposure: Previous asbestos exposure of the workers; fiber types and doses are not reported. The markers studied were blood GGT fractions (big, medium, small, free), measured by gel filtration chromatography. SMRP and plasma osteopontin (pOPN) were also measured, in exposed workers and mesothelioma cases only.
• Main results:
  • In the whole mesothelioma group (n = 37), big-GGT and medium-GGT activity differed significantly from both exposed workers and non-exposed subjects. Median big-GGT was 4.06 U/L in mesothelioma patients, 2.93 in exposed workers and 2.46 in non-exposed subjects (p = 0.020 versus workers; p = 0.001 versus non-exposed).
  • Big- and medium-GGT rose from non-exposed subjects to exposed workers to mesothelioma patients (p = 0.001). Free-GGT showed a decreasing trend that was not statistically significant. Median free-GGT was 11.84 U/L in non-exposed subjects, 11.04 in exposed workers and 11.06 in mesothelioma patients, and no pairwise comparison was significant.
  • Exposed workers had significantly higher big-GGT than non-exposed subjects (medians 2.93 vs 2.46 U/L, p = 0.004). They also had significantly higher medium-GGT (medians 0.70 vs 0.51 U/L, p = 0.002). The other fractions did not differ.
  • The big/free GGT ratio gave the best area under the curve among the GGT measures: 0.679 (95% CI 0.582 to 0.777, p = 0.001). For comparison, big-GGT alone gave 0.633 and total GGT gave 0.567 (not significant).
  • Median SMRP was 1.95 nM in mesothelioma patients and 0.88 nM in exposed workers (p less than 0.0001).
  • Combining SMRP with the big/free GGT ratio gave an area under the curve of 0.875 (95% CI 0.807 to 0.943) for distinguishing mesothelioma patients from exposed workers. At the best cut-off of 0.10, chosen with the Youden index, sensitivity was 87.50% and specificity was 72.19%.
  • In this cohort, the earlier SMRP plus osteopontin combination gave an area under the curve of 0.857 (95% CI 0.776 to 0.937). The SMRP plus big/free GGT combination was slightly higher at 0.875.
• The authors' conclusion: The authors concluded that epithelioid mesothelioma showed a specific pattern of GGT fraction activity, and that combining the big/free GGT ratio with SMRP increased diagnostic power. They stated the combined accuracy was still too low for clinical practice. They added that GGT fractions merit testing in future panels of early-diagnosis biomarkers.
• Limitations the authors state:
  • The number of mesothelioma cases was small.
  • Only the epithelioid subtype was studied. Mixed and sarcomatoid mesothelioma were excluded for lack of cases.
  • Information on other health conditions was available for only 19 of the 37 mesothelioma patients.
  • A larger sample is needed to better estimate the sensitivity and specificity of GGT as a mesothelioma biomarker.
  • The biological meaning of the GGT fractions is poorly understood, which limits interpretation of the findings.

Topics

Medical terms in this study, explained in our Lexicon: Biomarker, Mesothelioma, Pleural Mesothelioma, Latency, Prognosis, Mesothelin, Soluble Mesothelin-Related Peptides (SMRP).

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• Identification of miRNA-103 in the cellular fraction of human peripheral blood as a potential biomarker for malignant mesothelioma--a pilot study — D.G. Weber, G. Johnen, et al. (2012)
• Serum mesothelin and other biomarkers: what have we learned in the last decade? — A. Cristaudo, A. Bonotti, et al. (2018)
• Putative Biomarkers for Malignant Pleural Mesothelioma Suggested by Proteomic Analysis of Cell Secretome — S. Lacerenza, F. Ciregia, et al. (2020)
• Biomarkers in the prevention and follow-up of workers exposed to asbestos — R. Foddis, A. Bonotti, et al. (2018)
• A Novel Panel of Serum Biomarkers for MPM Diagnosis — A. Bonotti, R. Foddis, et al. (2017)

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