Genomic Mechanisms of Fatigue in Survivors of Colorectal Cancer

BACKGROUND: Many cancer survivors experience fatigue as a nagging symptom lasting years after treatment. To learn of the relevant biological pathways involved in fatigue among cancer survivors, the authors tested for an association between fatigue levels and leukocyte gene expression profiles and determined the specific mediating immune cell types. METHODS: A sample of 89 Hispanic/Latino adults aged 60.5 years, 62% of whom were male, who were diagnosed with colorectal cancer and were 2.9 years since diagnosis provided blood for transcriptome profiling and completed a validated measure of fatigue (Multidimensional Fatigue Symptom Inventory-Short Form). The authors applied genome-wide transcriptional profiling of leukocyte RNA to identify gene expression activity associated with fatigue, tested for the activity of specific transcription factors involved in previously established markers of inflammation and immunologic activation, and identified the specific cell types mediating these transcriptional alterations. RESULTS: In analyses adjusting for demographic and behavioral health risk factors, results linked fatigue with increased activation of B lymphocytes and CD8-positive T cells, as well as several transcription factors involved in immune activation (nuclear factor kappa B [NF-kappa B], signal transducer and activator of transcription [STAT], and cAMP responsive element-binding protein [CREB]). Results also replicated several specific genomic effects previously observed in fatigued cancer survivors, including upregulated expression of a-synuclein (SNCA) and hemoglobin subunits (HBA and HBB). CONCLUSIONS: Cancer survivors' heightened fatigue levels may be partially explained by activation of specific immune cell subsets, thereby providing a potential molecular biomarker for clinical interventions targeting the remediation of fatigue. (C) 2018 American Cancer Society.