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.
Highlights
Malignant pleural mesothelioma (MPM) is characterized by very long latency periods, sudden clinical onset, and extremely poor prognosis [1]
Some in vitro studies showed that neoplastic epithelial cell lines other than the liver, including melanoma, prostate cancer, and bronchial epithelium, release GGT activity in the medium mainly as a b-GGT-fraction, explaining the increase in serum GGT observed in diseases of other organs [11]
The median and distribution values of the two non-neoplastic groups did not differ for any fractions except for the b-GGT and m-GGT, with the median of ne-HS being significantly lesser than the pe-W (Table 2)
Summary
Malignant pleural mesothelioma (MPM) is characterized by very long latency periods, sudden clinical onset, and extremely poor prognosis [1]. We showed that exposure to a subtoxic concentration of crocidolite asbestos triggered a GGT overexpression in THP-1 macrophagic cells, suggesting the possible involvement of GSH/GGT-dependent prooxidant reactions in the pathogenesis of MPM [8]. For this reason, GGT could be a diagnostic marker for MPM. BGGT presents the best sensitivity and specificity for the diagnosis of steatosis, while s-GGT is more suited for chronic viral hepatitis [10] These first results have raised the interest for GGT fractional enzymatic activity in other medical fields. Some in vitro studies showed that neoplastic epithelial cell lines other than the liver, including melanoma, prostate cancer, and bronchial epithelium, release GGT activity in the medium mainly as a b-GGT-fraction, explaining the increase in serum GGT observed in diseases of other organs [11]
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