Exchangeable Copper Excess and Zinc Deficiency in the Serum of Patients with Colorectal Cancer

Copper (Cu) and Zinc (Zn) are altered in colorectal cancer (CRC) but their association with the clinical classification of the tumor has not been fully explored. To examine the association of Cu and Zn homeostasis in the onset and severity of CRC, we performed an exploratory case-control study comparing the serum levels for Cu, the exchangeable component of Cu in serum (CuExc), Zn, the ratio between them (CuExc:Zn), ceruloplasmin [Cp, concentration (iCp) and its activity (eCp), Cp specific activity (eCp:iCp)], and the Cu:Cp, assessed in 31 consecutive CRC patients before surgical resection to those obtained from 37 healthy controls (CTRL). Additionally, we correlated the analyte levels with the indices of the pathological tumor, node, and metastasis (TNM) staging, namely tumor (T), node (N), and metastasis (M), evaluated at the histopathological examination. We found that Cu, CuExc, CuExc:Zn, iCp, eCp, eCp:iCp, and Cu:Cp ratios increased while Zn decreased in CRC patients. In addition, correlation analyses showed that CuExc and Zn levels confirmed the CRC diagnosis. Specifically, CuExc:Zn further increased the discrimination between the individuals of the two groups, providing an area under the curve (ROC AUC) = 0.94. Elevated CuExc was the strongest factor associated with CRC resulting in 15-fold increased odds. These data were confirmed through a multivariable regression model revealing an effect of Zn and CuExc on the CRC risk, with the CuExc resulting in 11-fold increased odds of having the disease. We also found that most of the Cu biological variables analyzed were associated with T, while the CuExc was associated with M. The current pilot study demonstrates that excess labile Cu pool, Zn deficiency, and even further their combination in the CuExc:Zn provide information about CRC in terms of diagnosis, risk of having CRC, and CRC disease stage.