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

Agustina A M B Hastuti,Takayuki Ichinose,Frank Vanhaecke,Marta Costas-Rodríguez,Mari Shimura,Shotaro Hagiwara,Akihiro Matsunaga

doi:10.1038/s41598-020-71764-7

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.

Highlights

We have examined potential changes in the isotopic compositions of Fe, Cu and Zn and the corresponding concentrations in plasma from hematological malignancy (HM) patients and assessed their prognostic capability
Patients suffering from HMs, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), multiple myeloma (MM) and non-Hodgkin’s lymphoma (NHL), were recruited from the hospital of the National Center for Global Health and Medicine (NCGM) in Tokyo, Japan
The Fe, Cu and Zn isotopic compositions in blood plasma, serum, red blood cells or whole blood of healthy individuals from different geographical origins have been documented, data are still scarce and only a few works reported the isotopic composition of the three elements for the same sample/individual[17, 18]

Summary

Introduction

We have examined potential changes in the isotopic compositions of Fe, Cu and Zn (using multicollector 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. Variations in stable isotope ratios of essential mineral elements have been shown to reflect alterations in their homeostasis due to physiological changes in malignancies with higher sensitivity than concentrations do. The serum and whole blood Cu isotopic compositions have been shown to be significantly lighter (enriched in the light 63Cu isotope) in breast cancer, colorectal cancer[12], and hepatocellular carcinoma p atients[13] compared to controls. No differences were established in the serum and whole blood Zn isotopic composition in breast cancer[15], colon cancer, and prostate cancer p atients[11] compared to that of controls, but the breast tumour tissue was shown to be enriched in the light 64Zn isotope compared to healthy t issue[15]. Metal isotopic compositions may reflect changes in metal homeostasis with higher sensitivity than metal concentrations do, such that high-precision isotopic analysis can detect physiological abnormalities at an early s tage[12, 16]

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Discussion

Conclusion