Copper isotope effect in serum of cancer patients. A pilot study.

The isotope effect describes mass-dependent variations of natural isotope abundances for a particular element. In this pilot study, we measured the (65)Cu/(63)Cu ratios in the serums of 20 breast and 8 colorectal cancer patients, which correspond to, respectively, 90 and 49 samples taken at different times with molecular biomarker documentation. Copper isotope compositions were determined by multiple-collector inductively coupled plasma mass spectrometry (MC-ICP-MS). When compared with the literature data from a control group of 50 healthy blood donors, abundances of Cu isotopes predict mortality in the colorectal cancer group with a probability p = 0.018. For the breast cancer patients and the group of control women the probability goes down to p = 0.0006 and the AUC under the ROC curve is 0.75. Most patients considered in this preliminary study and with serum δ(65)Cu lower than the threshold value of -0.35‰ (per mil) did not survive. As a marker, a drop in δ(65)Cu precedes molecular biomarkers by several months. The observed decrease of δ(65)Cu in the serum of cancer patients is assigned to the extensive oxidative chelation of copper by cytosolic lactate. The potential of Cu isotope variability as a new diagnostic tool for breast and colorectal cancer seems strong. Shifts in Cu isotope compositions fingerprint cytosolic Cu chelation by lactate mono- and bidentates. This simple scheme provides a straightforward explanation for isotopically light Cu in the serum and isotopically heavy Cu in cancer cells: Cu(+) escaping chelation by lactate and excreted into the blood stream is isotopically light. Low δ(65)Cu values in serum therefore reveal the strength of lactate production by the Warburg effect.