Serum Calretinin as a Biomarker in Malignant Mesothelioma

Abstract

The early diagnosis of malignant mesothelioma (MM) could improve the prognosis of MM patients. To confirm an MM diagnosis, an immunohistochemical analysis of several tumor tissue markers, including calretinin, is currently required. Our aim is to evaluate serum calretinin as a potential biomarker in asbestos-related diseases, especially in MM. Our study includes 549 subjects: 164 MM patients, 117 subjects with asbestosis, 195 subjects with pleural plaques and 73 occupationally asbestos-exposed subjects without asbestos-related diseases. The serum calretinin concentration was determined with a commercially available enzyme immunoassay. Data on the soluble mesothelin-related peptides (SMRP) concentration are available from previous studies. MM patients had a significantly higher calretinin concentration than subjects without disease, subjects with pleural plaques or subjects with asbestosis (all p < 0.001). The histological type was significantly associated with serum calretinin: patients with sarcomatoid MM had lower calretinin than patients with the epithelioid type (p = 0.001). In a ROC curve analysis, the area under the curve for calretinin concentration predicting MM was 0.826 (95% CI = 0.782–0.869; p < 0.001). At the cutoff value of 0.32 ng/mL, sensitivity was 0.683, while specificity was 0.886. The combination of calretinin and SMRP had the highest predictive value. Calretinin is a useful biomarker that can distinguish MM from other asbestos-related diseases and could, therefore, contribute to an earlier non-invasive diagnosis of MM.

Serum Calretinin and Genetic Variability as a Prognostic and Predictive Factor in Malignant Mesothelioma

“…A calretinin concentration above 0.89 ng/mL was a good predictor of disease control rate and survival, but not response rate, suggesting that it is associated more with disease progression. This concentration is much higher than the concentration of 0.32 ng/mL, which could be used as a diagnostic biomarker to discriminate between MM patients and other asbestos-exposed subjects based on our previous results [ 18 ].…”

“…So far, the association between tissue calretinin expression and soluble calretinin in MM was only investigated in one study: patients with calretinin-positive tumors had higher plasma calretinin [ 29 ], and, therefore, a similar prognostic role in tissue and blood could be expected. However, the positive correlation of calretinin expression in tissue and plasma could be attributed to the fact that calretinin is more often detected in epithelioid and biphasic MM compared to the sarcomatoid subtype in both tissue and plasma or serum of MM patients [ 18 , 20 , 30 , 31 ]. As patients with sarcomatoid MM still have much shorter survival [ 32 ], this could explain the observed differences regarding the association of calretinin with survival.…”

“…Serum samples were collected at diagnosis, prepared within 6 h of blood collection, and stored at −20 °C until analysis. Serum calretinin concentrations were determined using a commercially available enzyme-linked immunosorbent calretinin ELISA assay (DLD Diagnostika GmbH, Hamburg, Germany) according to the manufacturer’s instructions, as previously described [ 18 , 20 , 42 ]. The manufacturer reported the intra-assay coefficient of variation as 8.1–6.6% and the inter-assay coefficient of variation as 10.4–10.0%.…”

“…It can also be found in serum, plasma, and pleural effusions of MM patients, as well as extracellular vesicles (EVs) derived from MM cell lines [ 16 , 17 ]. Calretinin plasma or serum concentration is higher in patients with MM than healthy people or patients with benign asbestos-related diseases [ 16 , 18 , 19 , 20 ] and it could, therefore, also contribute to an earlier non-invasive diagnosis of MM as a circulating biomarker [ 18 ].…”

The association of genetic factors with serum calretinin levels in asbestos-related diseases

“…20 Higher calretinin concentrations were observed in patients with epithelioid or biphasic MM compared to patients with sarco-matoid MM. 8,20,21 Calretinin levels were also higher in women compared to men and in subjects with renal dysfunction. 22 Molecular mechanisms regulating calretinin expression in various tissues or in cancer could also contribute to interindividual variability of serum calretinin concentration, but the knowledge of these processes is limited.…”