Cytokine genetic variations and fatigue among patients with breast cancer

Abstract

Purpose: Fatigue is a common adverse effect of cancer treatment and may persist for years after treatment completion. However, risk factors for post-treatment fatigue have not been determined. On the basis of studies suggesting an inflammatory basis for fatigue, this study tested the hypothesis that expression-regulating polymorphisms in proinflammatory cytokine genes would predict post-treatment fatigue in breast cancer survivors. Patients and Methods: Women diagnosed with early-stage breast cancer (n 171) completed questionnaires to assess fatigue and other behavioral symptoms (ie, depressive symptoms, memory complaints, sleep disturbance) and provided blood for genotyping within 3 months after primary treatment. Genomic DNA was extracted from peripheral-blood leukocytes and assayed for single nucleotide polymorphisms (SNPs) in the promoter regions of three cytokine genes: ILB 511 CT (rs16944), IL6 174 GC (rs1800795), and TNF 308 GA (rs1800629). An additive genetic risk score was computed by summing the number of high-expression alleles (zero, one, or two) across all three polymorphisms. Results: The genetic risk index was significantly associated with fatigue; as the number of high-expression alleles increased, so did self-reported fatigue severity (P .002). Analyses of individual SNPs showed that TNF 308 and IL6 174 were independently associated with fatigue (P .032). The genetic risk index was also associated with depressive symptoms (P .007) and memory complaints (P .016). Conclusion: These findings further implicate inflammatory processes as contributors to cancer-related fatigue and suggest a new strategy for identifying and treating patients at risk for this symptom based on genetic variants in proinflammatory cytokine genes.