Abstract
ObjectiveExpression of pro-inflammatory cytokines is influenced by single nucleotide polymorphisms (SNPs) in the promoter regions of the pro-inflammatory cytokine genes, and cytokines are associated with the occurrence of post-chemotherapy cognitive impairment. Hence, the aim of this study was to evaluate the associations between two common pro-inflammatory cytokine gene polymorphisms namely, IL6-174 (rs1800795 G>C) and TNF-308 (rs1800629 G>A), and chemotherapy-associated cognitive impairment (CACI) among Asian early-stage breast cancer patients. In addition, the differential effect of these SNPs on plasma IL-6 and TNF-α levels, and the associations of plasma IL-6 and TNF-α levels with CACI were also assessed.MethodsAsian early-stage breast cancer patients (Stage I to III) receiving chemotherapy were prospectively recruited from two cancer centers in Singapore. Patients' cognitive function was longitudinally assessed using the validated FACT-Cog (ver. 3) and an objective computerized battery, Headminder™ at three-time points. Plasma IL-6 and TNF-α levels were analyzed using the multiplex immunoassay, and genotyping was performed using Sanger sequencing. Regression analyses and generalized estimating equation were utilized for statistical analysis.ResultsA total of 125 patients were included (mean age: 50.3; Chinese: 80.8%; post-menopausal: 48.0%; 68.0% received anthracycline-based chemotherapy). 36.8% patients experienced self-perceived cognitive impairment, detected in memory (32.8%) and attention (34.2%) domains. Patients with higher levels of anxiety (p<0.001) and insomnia (p = 0.003) also reported more self-perceived cognitive impairment. Higher plasma concentrations of IL-6 were associated with greater severity of self-perceived cognitive impairment (p = 0.001). Polymorphisms of cytokine genes were not associated with expression of plasma cytokines.ConclusionPresent findings further contribute to the growing evidence that supports the role of the pro-inflammatory cytokine IL-6 in the occurrence of cognitive impairment post-chemotherapy. However, genetic polymorphism of these cytokines did not play a major role to the cytokine fluctuations as well as cognitive impairment in this cohort. With an increasing evidence to support the cytokine hypothesis, future studies should investigate the role of anti-inflammatory agents in mitigating the cognitive impairment associated with chemotherapy.
Highlights
On the physiological level, inflammatory cytokines play important roles in the central nervous system (CNS) to modulate neuronal and glial cell functioning and neuronal repair [1,2,3]
The Downstream Effects of Genetic Polymorphism on Cytokine Plasma Levels, and Cognitive Impairment had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
Present findings further contribute to the growing evidence that supports the role of the proinflammatory cytokine IL-6 in the occurrence of cognitive impairment post-chemotherapy
Summary
Inflammatory cytokines play important roles in the central nervous system (CNS) to modulate neuronal and glial cell functioning and neuronal repair [1,2,3]. In patients with cancer, such inflammation cascade is speculated to increase one’s risk for subtle changes in cognition. This phenomenon is known as cancer-associated cognitive impairment (CACI) or ‘chemobrain’ in the literature. The TNF-308 G>A (rs1800629) polymorphism has been associated with high transcriptional activity, which increases the secretion levels of TNF-α, whereas the IL6174 G>C (rs1800795) polymorphism has been reported to influence the expression of IL-6, with carriers of the G allele being associated with higher plasma concentrations of IL-6 [4,5,6]. Another study suggested that carriers of high-expression alleles of IL6-174 and TNF-308 were associated with poorer memory in breast cancer patients [8]. Current findings suggest that host genetic factors could contribute to differential expression of the pro-inflammatory cytokines, which in turn translate to varying degrees of susceptibility to CACI among patients
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