Biomarker-based profiling of fatigue in childhood cancer survivors: evidence for distinct inflammatory and glial-associated profiles

Abstract

Background

Fatigue is a prevalent and burdensome late effect in childhood cancer survivors (CCS), yet its biological underpinnings remain poorly understood. This study examined associations between fatigue and blood-based biomarkers in CCS compared to healthy controls (HCs) and explored whether biologically distinct CCS profiles with respect to fatigue could be identified.

Procedure

Eighty CCS (aged 14–28) and 35 age- and sex-matched HCs provided blood samples and completed the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (PedsQL-MFS). Plasma concentrations of 12 biomarkers (e.g., IL-2, TNF-α, BDNF, Total Tau, NfL, MCP-1, GFAP) were quantified using Meso Scale Discovery immunoassays. Analyses included group comparisons, Spearman correlations, and unsupervised clustering (hierarchical and k-means).

Results

CCS reported significantly higher fatigue than HCs and showed significantly elevated levels of GFAP (d = 0.43), MCP-1 (d = 0.74), and Total Tau (d = 0.54). No individual biomarkers differentiated fatigued from non-fatigued CCS. Clustering revealed two biomarker-based CCS subgroups: one with high levels of inflammatory and neurodegenerative markers, and one with lower levels, yet fatigue severity was comparable. Within-cluster analyses showed distinct patterns: in the low-biomarker group, fatigue was associated with GFAP (ρ = −0.26 and ρ = −0.27, p < 0.05), whereas in the high-biomarker group, fatigue was more consistently linked to IL-8, IL-1α, and TNF-α (ρ = −0.38 to −0.49, p < 0.05).

Conclusion

Findings suggest that fatigue in CCS may be associated with distinct biological pathways, including astrocyte-linked processes in one subgroup and systemic inflammation in another. This suggests the need for more personalized, biomarker-informed strategies to understand and manage fatigue in pediatric cancer survivorship.