Cu and Zn isotope ratio variations in plasma for survival prediction in hematological malignancy cases

Abstract

We have examined potential changes in the isotopic compositions of Fe, Cu and Zn (using multi-collector inductively coupled plasma-mass spectrometry) and the corresponding concentrations (using inductively coupled plasma-atomic emission spectrometry) in plasma from hematological malignancy (HM) patients and assessed their prognostic capability. Together with clinical laboratory test values, data were examined in view of a 5-years survival prediction. Plasma Cu and Zn isotope ratios and their concentrations were significantly different in HM patients compared to matched controls (P < 0.05). Both δ65Cu and δ66Zn values showed significant mortality hazard ratios (HRs) in HM. The group of patients with decreased δ65Cu and increased δ66Zn values showed significantly poorer survival from the early phase (HR 3.9; P = 0.001), forming a unique cohort not identified based on laboratory test values. Well-known prognostic factors for HM, such as the creatinine level, and anemia-related values were highly correlated with the δ66Zn value (P < 0.05). Time-dependent ROC curves based on the δ65Cu or δ66Zn value were similar to that based on the creatinine concentration (a well-known prognostic factor in HM), indicating that δ65Cu or δ66Zn values are useful for prognosis of HM. Variations in stable isotope ratios of essential mineral elements have thus been shown to reflect alterations in their homeostasis due to physiological changes in malignancies with higher sensitivity than concentrations do.

Cu, Fe, and Zn isotope ratios in murine Alzheimer's disease models suggest specific signatures of amyloidogenesis and tauopathy

“…High-precision isotopic analysis is being explored as a diagnostic tool for diseases that can otherwise only be established at a later stage and/or via more invasive techniques, or for obtaining a more profound insight into biochemical processes involving the element of interest ( 37 , 38 ). So far, the isotopic composition of Cu was proven to be useful in the context of liver disease ( 39 ) and cancer ( 40 , 41 ), that of Fe as a robust marker of individual Fe status, also in cases in which the currently used markers are no longer reliable ( 42 , 43 ), and that of Zn in cancer ( 41 , 44 , 45 ). High-precision isotopic analysis has also been successfully applied in animal experiments to contribute to further insight into the factors governing the differences in isotopic composition ( 46 , 47 , 48 ).…”

High‐precision isotopic analysis of essential mineral elements: capabilities as a diagnostic/prognostic tool

“…Chemotherapy could, for example, also put a huge strain on the liver, which might contribute to the shift in the whole blood/serum isotope ratio observed. However, some studies explicitly report that the cancer patients did not receive any chemotherapeutic treatment at the time of sampling, 39,44 whereas the observation of a local heavier isotopic composition in tumoral tissue has been a consequent observation 20,38–40 …”

“…Schilling et al reported that the isotopic composition of urine Zn in pancreatic cancer is shifted to a lower value 43 . By calculating hazard ratios and constructing time‐dependent receiver operating characteristic (ROC) curves, Hastuti et al 44 demonstrated the isotopic composition of Cu and Zn in plasma to be useful for the prediction of survival among hematological malignancy patients. Patients displaying a lighter Cu isotopic composition and a heavier Zn isotopic composition in plasma showed the poorest survival.…”

Modulation of Intracellular Copper Levels as the Mechanism of Action of Anticancer Copper Complexes: Clinical Relevance

“…It was suggested that heavy 65 Cu isotope was preferentially chelated in cancer cells with the subsequent release of lighter 63 Cu into bloodstream [ 46 , 47 ]. However, analysis of 65 Cu in patients with hematological malignancies revealed similar decrease of heavier Cu isotope in blood of cancer patients in comparison with healthy controls [ 48 ]. The changes in Cu isotopic pattern in cancer patients were also linked to Warburg effect.…”

“…In contrast to Cu, the differences in Zn isotopic distribution in cancer patients and healthy controls were less informative. It was shown that blood plasma of cancer patients with hematologic malignancies was characterized by higher abundance of heavier isotopes than in healthy people [ 48 ]. However, resections of breast tumors revealed lighter Zn isotopic content than healthy breast tissues, while serum of breast and colon cancer patients and healthy individuals could not be differentiated [ 46 , 49 , 50 ].…”