Transcriptomic Profiles and Functional Correlates of Cancer-Related Fatigue: A Cross-Sectional Study in Women Undergoing Cancer Treatment

Abstract

Background and Objectives: Cancer-related fatigue is a multifactorial condition that affects most people undergoing chemotherapy. To elucidate potential biological underpinnings of fatigue, this study tested correlations between patient-reported fatigue and (1) functional measures and (2) transcriptomics of whole blood.

Methods: Women undergoing chemotherapy were recruited to a cross-sectional study. Participants reported subjective fatigue on the Functional Assessment for Chronic Illness Therapy-Fatigue (FACIT-F) and Brief Fatigue Inventory (BFI) questionnaires. Participants completed upper- and lower-body functional assessments as an objective fatigability measure. Fasted blood samples were analyzed for complete blood counts (CBCs) to quantify cell type, and RNA-Seq on whole blood was investigated for a distinct transcriptional signature in patients with high vs. low fatigue. Principal component analysis revealed that transcriptomic profiles clustered based on the neutrophil level, lymphocyte level, and several other clinical factors, which were accounted for when assessing differentially expressed genes.

Results: Participants had breast (n = 29) or uterine (n = 1) cancer, were 53.4 ± 13.5 years old, and identified as Black/African American (56%) or White (44%). Hand grip strength, static fatigue index, and sit-to-stand assessments were not associated with FACIT-F fatigue subscale responses. From RNA-Seq data, higher fatigue was associated with fewer SH3RF1 transcripts (p = 4.1e-3) and more CAPRIN2 transcripts (p = 8.2e-3). Unbiased gene ontology/pathway analyses revealed perturbed biological processes in mitochondrial function, chiefly aerobic respiration (normalized effect size [ES] = −2.1), electron transport chain (ES = −1.9), generation of precursor metabolites and energy (ES = −1.8), and fatty acid oxidation (ES = −2.0), which tended to be downregulated among participants with more fatigue. Cellular components analyses consistently showed downregulation of mitochondrial proteins among those with higher fatigue (ESs = −1.7–−2.2). Future studies should investigate dietary, physical activity, and/or pharmaceutical interventions to optimize the efficiency of mitochondrial energy production during treatment to mitigate fatigue.