Biological correlates of cancer-related fatigue in older male cancer survivors

Older male cancer survivors often experience chronic fatigue. Although the pathogenesis of cancer-related fatigue (CRF) remains unclear, circulating inflammatory markers and gene expression profiles may provide insights into the underlying biological mechanisms of persistent CRF. We examined the potential biological correlates of CRF in older male cancer survivors. This is a secondary analysis of baseline data from a randomized controlled trial that examined the effects of Tai Chi Qigong on fatigue and inflammation biology among 107 older male cancer survivors (≥ 55 years). Fatigue was assessed with the Functional Assessment of Chronic Illness-Fatigue Scale. Blood samples were collected for circulating inflammatory biomarkers (C-reactive protein, IL-6, IL-8, IL-10, IFN-γ, TNF-α), and for genome-wide transcriptional profiling. Pearson's correlation and multivariable linear regression were used to assess these relationships while adjusting for sociodemographic and clinical factors. Due to multiple testing, false discovery rate-corrected p-values were reported. Worse fatigue was significantly associated with higher levels of CRP (p = 0.011), IL-6 (p = 0.002), and TNF-α (p = 0.010). Fatigue was also significantly correlated with increased expression of three immune-related genes, namely [CXCR4 (p = 0.023), IRF-7 (p = 0.009), and TGM2 (p = 0.018)], one mitochondrial-related gene [HSPA2 (p = 0.001)], one transcription factor gene [ETS1 (p = 0.037)], one neuropeptide [OPRL1 (0.036)], and decreased expression of two immune-related genes [LY6E (p = 0.029), COMMD9 (p = 0.034)], and three RNA/DNA processing genes [SNORD89 (p < 0.001), TFIP11 (p = 0.017), and UNG (p = 0.003)]. CRF was associated with inflammatory profiles and coordinated transcriptional shifts involving immune activation, neuro-immune signaling, mitochondrial dysfunction, and impaired nucleic acid processing, thereby offering a coherent biological context for CRF in this population. Clinical Trial Registration: The HERO Trial was registered in the NIH Clinical Trials Registry on November 17, 2017 (NCT03345563).