Department of Psychology, University of California, Los Angeles, CA 90095-1563, USA.
J Clin Oncol. 2013 May 1;31(13):1656-61. doi: 10.1200/JCO.2012.46.2143. Epub 2013 Mar 25.
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.
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.
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).
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.
疲劳是癌症治疗的常见不良反应，并且在治疗完成后可能会持续数年。但是，尚未确定治疗后疲劳的危险因素。基于研究表明疲劳的基础是炎症，本研究检验了这样一种假设，即促炎细胞因子基因表达调节多态性将预测乳腺癌幸存者治疗后的疲劳。
在初次治疗后 3 个月内，被诊断患有早期乳腺癌的女性（n = 171）完成了评估疲劳和其他行为症状（即抑郁症状、记忆问题、睡眠障碍）的问卷，并提供血液进行基因分型。从外周血白细胞中提取基因组 DNA，并对三个细胞因子基因的启动子区域的单核苷酸多态性（SNP）进行检测：ILB-511 C>T(rs16944)、IL6-174 G>C(rs1800795)和 TNF-308 G>A(rs1800629)。通过对所有三个多态性中高表达等位基因（零、一或二）的数量求和，计算出遗传风险评分。
遗传风险指数与疲劳显著相关；随着高表达等位基因数量的增加，自我报告的疲劳严重程度也增加（P =.002）。对单个 SNP 的分析表明，TNF-308 和 IL6-174 与疲劳独立相关（P =.032）。遗传风险指数还与抑郁症状（P =.007）和记忆问题（P =.016）相关。
这些发现进一步表明炎症过程是癌症相关疲劳的原因，并提出了一种基于促炎细胞因子基因中的遗传变异来识别和治疗有此症状风险的患者的新策略。
