Genomic Profile of Fatigued Men Receiving Localized Radiation Therapy

The purpose of this study was to explore gene expression changes in fatigued men with nonmetastatic prostate cancer receiving localized external beam radiation therapy (EBRT).

Fatigue was measured in 40 men with prostate cancer (20 receiving EBRT and 20 controls on active surveillance) using the Functional Assessment of Cancer Therapy-Fatigue (FACT-F). EBRT subjects were followed from baseline to midpoint and end point of EBRT, while controls were seen at one time point. EBRT subjects were categorized into high- and low-fatigue groups based on change in FACT-F scores from baseline to EBRT completion. Full genome microarray was performed from peripheral leukocyte RNA to determine gene expression changes related to fatigue phenotypes. Real-time polymerase chain reaction and enzyme-linked immunosorbent assay confirmed the most differentially expressed gene in the microarray experiment.

At baseline, mean FACT-F scores were not different between EBRT subjects (44.3 ± 7.16) and controls (46.7 ± 4.32, p = .24). Fatigue scores of EBRT subjects decreased at treatment midpoint (38.6 ± 9.17, p = .01) and completion (37.6 ± 9.9, p = .06), indicating worsening fatigue. Differential expression of 42 genes was observed between fatigue groups when EBRT time points were controlled. Membrane-spanning four domains, subfamily A, member (MS4A1) was the most differentially expressed gene and was associated with fatigue at treatment end point (r = -.46, p = .04).

Fatigue intensification was associated with MS4A1 downregulation, suggesting that fatigue during EBRT may be related to impairment in B-cell immune response. The 42 differentially expressed fatigue-related genes are associated with glutathione biosynthesis, γ-glutamyl cycle, and antigen presentation pathways.