CUPID-ALL: Copper Elevation, Protective Micronutrient Depletion And Environmental Toxicant Burden In Pediatric Acute Lymphoblastic Leukemia

Background and Aims: Trace elements influence oxidative stress, immune regulation, cellular metabolism and genomic stability. However, comprehensive trace element profiling in pediatric Acute Lymphoblastic Leukemia (ALL) remains limited. We evaluated trace element signatures in children with ALL and multiple control populations.

Methods: Serum concentrations of barium, cobalt, chromium, copper, manganese, nickel, selenium, uranium, vanadium, zinc and aluminium, and whole blood concentrations of beryllium, gallium, arsenic, mercury, cadmium, lead, thallium and strontium were quantified by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). Children with ALL (n=120) were compared with healthy controls (n=55), sibling controls (n=23), non-leukemic disease controls (n=25) and an independent non-northern ALL cohort (n=7).

Results: Eleven of nineteen elements remained significantly altered after False Discovery Rate (FDR) correction. Copper demonstrated the strongest positive association with ALL (FDR<0.0001), while selenium showed the greatest reduction (FDR<0.0001). Lead (FDR=0.0001), aluminium (FDR=0.0006), mercury (FDR=0.0016) and uranium (FDR=0.0053) were significantly elevated in ALL. In contrast, selenium (FDR<0.0001), arsenic (FDR=0.0006), gallium (FDR=0.0017), cobalt (FDR=0.0018), chromium (FDR=0.0019) and zinc (FDR=0.0341) were significantly reduced. Elevated copper together with reduced selenium and zinc resulted in markedly increased Cu/Se and Cu/Zn ratios (both FDR<0.0001), representing the strongest discriminatory biomarkers. Lead and mercury were elevated in both ALL cases and sibling controls, suggesting potential shared environmental exposure. Mercury elevation in pediatric ALL has not been previously reported. Similar elemental patterns were observed in the independent non-northern ALL cohort.  

Conclusions: Pediatric ALL is associated with a distinct trace element signature characterized by copper elevation, depletion of protective micronutrients and evidence of environmental toxicant exposure. These findings support further investigation of oxidative stress, cuproptosis pathways, mutational burden and mutational signatures in ALL. Several elements also differed substantially from currently accepted pediatric reference intervals, highlighting the need for population-specific reference ranges

Sharun is a PhD candidate in the Department of Paediatrics at the Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, under the supervision of Dr. Prateek Bhatia. Her research focuses on pediatric leukemia, with a particular emphasis on genomic and metabolomic profiling for biomarker discovery and therapeutic response prediction after the environmental exposure to toxic compounds. She has experience in next-generation sequencing, bioinformatics, and molecular diagnostics, contributing to studies aimed at improving early detection and treatment outcomes in childhood leukemia.