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 C>T (rs16944), IL6 −174 G>C (rs1800795), and TNF −308 G>A (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.

Incremental Prognostic Value of Echocardiographic Strain and Its Association With Mortality in Cancer Patients

“…CRF and cachexia are both associated with elevated inflammatory cytokines. [17][18][19][20] In addition, cachexia has been noted to cause myocardial dysfunction in animal models. [21] High levels of inflammatory cytokines are associated with a poor prognosis in cancer patients and with worsening cardiac disease including systolic dysfunction in more general cohorts.…”

Genetic polymorphisms associated with common symptoms experienced by breast cancer patients

“…Their results demonstrated that fatigue was significantly associated with both TNF-308 and IL6-174 but was not associated with IL1B-511 C>T. The addition of TNF-308 previously established to be associated with fatigue among oncology patients undergoing treatment [62] might have enhanced the sensitivity of Bower et al study to detect SNPs association with fatigue. Although this recent study [61] suggests that breast cancer patients harbouring certain variants of cytokines genes may be at higher risk of developing fatigue, it still cannot be concluded at this point if genetic variants of pro-inflammatory cytokines could serve as clinical genetic biomarkers to predict breast cancer patients who have higher risk of having fatigue. Indeed, more studies involving additional genetic variants especially in a larger cohort of different ethnicities are needed.…”

“…The roles of pro-inflammatory cytokines genetic polymorphisms in developing breast cancer-associated depression was further provided by Bower et al who established that breast cancer patients with heterozygous GG genotype of IL6-174 SNP experienced higher depressive symptoms when compared with those carrying the GC and CC genotypes [61]. Another similar study [75] reported that breast cancer patients who were homozygous for a rare allele variant of TNF-α (rs1799964) had lower odds of developing subsyndromal depression.…”

“…Furthermore, patients heterozygous or homozygous for IL1R1 (rs2110726) rare variants had decreased odds of belonging to the "lower energy" group. To this point, the results of the Genetic polymorphisms associated with common symptoms experienced by breast cancer patients association between IL1B (rs16944) and the development of fatigue remain contradictory where a study [54] reported increased while the other [59] reported decreased likelihood of belonging to the fatigued group in patients carrying the rare variant allele while two other studies reported no significant association [60,61].…”

“…To further clarify the above contradictions, Bower et al examined TNF-308 G>A (rs1800629) together with IL1B-511 C>T and IL6-174 G>C discussed above among women with early-stage breast cancer [61]. Their results demonstrated that fatigue was significantly associated with both TNF-308 and IL6-174 but was not associated with IL1B-511 C>T. The addition of TNF-308 previously established to be associated with fatigue among oncology patients undergoing treatment [62] might have enhanced the sensitivity of Bower et al study to detect SNPs association with fatigue.…”