Epigenetics and Psychoneurologic Symptoms in Women with Breast Cancer

虽然乳腺癌治疗的进步提高了生存率，但大多数乳腺癌（BC）女性在治疗期间都会出现令人痛苦的症状，对一些人来说，这些症状会持续到生存期。BC妇女中最常报告的症状包括认知功能障碍（CD）、抑郁症状、焦虑、疲劳、睡眠障碍和疼痛，这些症状可统称为“精神神经（PN）症状”。“炎症激活和表观遗传改变与癌症的病因学和各种慢性神经认知障碍有关。然而，迄今为止，没有研究者认为这些表观遗传过程可能与BC女性PN症状的病因学相关。鉴于表观遗传模式已被证明具有可塑性，进一步阐明表观遗传改变与PN症状的发展和持续性的关系可以为未来开发预测标记物和治疗方法提供基础知识，以解决BC女性中与PN症状相关的表观遗传变化。 因此，本研究的具体目的是审查： 1. PN症状的频率和严重程度以及每个时间点PN症状之间的相互关系。 2.炎症水平，并量化化疗后一段时间内表观遗传模式变化的频率和全基因组定位。 3.炎症、表观遗传变化与PN症状随时间的发展、严重程度和持续性之间的关系。 为了实现这些目标，拟定的研究将前瞻性描述PN症状（认知功能障碍;抑郁症状和焦虑;疲劳;睡眠障碍;疼痛），炎症激活[（C-反应蛋白（CRP）、肿瘤坏死因子α（TNF-α）、白细胞介素1 β（IL-1B）和白细胞介素6（IL- 6）水平），和表观遗传学改变在5个时间点诊断为早期BC的75名妇女中：在接受化疗之前，在第四次化疗治疗时，以及在开始化疗后6，12和24个月。将通过定量以下指标来检测表观遗传改变：（1）甲基化的频率和全基因组位置;（2）组蛋白甲基转移酶EZH 2的表达，EZH 2是一种Polycomb组蛋白，被认为对表观遗传“决定”过程的早期步骤很重要;和（3）端粒磨损，可导致染色质压实/基因表达的改变。研究结果可能会加深对PN症状相关生物学过程的理解，并改善BC女性的症状管理策略。

Although advancements in breast cancer treatments have resulted in improved rates of survival, a majority of women with breast cancer (BC) experience distressing symptoms during treatment, which for some, persist into survivorship. The symptoms most frequently reported among women with BC include cognitive dysfunction (CD), depressive symptoms, anxiety, fatigue, sleep disturbances, and pain, which may be collectively called "psychoneurological (PN) symptoms." Inflammatory activation and epigenetic alterations have been associated with the etiology of cancer and with various chronic neurocognitive disorders. However, to date, no investigators have considered these epigenetic processes as possible mechanisms associated with the etiology of PN symptoms in women with BC. Given that epigenetic patterns have been shown to have plasticity, the further elucidation of the relationship of epigenetic alterations to the development and persistence of PN symptoms could provide foundational knowledge for the future development of predictive markers and treatments to address the epigenetic changes associated with PN symptoms in women with BC. Therefore, the specific aims of this study are to examine: 1. The frequency and severity of PN symptoms and the interrelationships among PN symptoms at each time point. 2. Levels of inflammation and to quantify the frequency and genome-wide localization of changes in epigenetic patterns across time following chemotherapy. 3. The relationships among inflammation, epigenetic changes, and the development, severity, and persistence of PN symptoms across time. To meet these aims, the proposed study will prospectively characterize PN symptoms (cognitive dysfunction; depressive symptoms and anxiety; fatigue; sleep disturbances; pain), inflammatory activation [(levels of C- reactive protein (CRP), tumor necrosis factor alpha (TNF-a), interleukin 1 beta (IL-1B), and interleukin 6 (IL- 6)], and epigenetic alterations in 75 women diagnosed with early-stage BC across 5 timepoints: prior to their receipt of chemotherapy, at the time of their fourth chemotherapy treatment, and at 6, 12, and 24 months following the initiation of chemotherapy. Epigenetic alterations will be detected by quantifying the: (1) frequency and genome-wide location of methylation; (2) expression of a histone methyltransferease, EZH2, which is a Polycomb group protein that is thought to be important for the early steps in the epigenetic "decision" process; and (3) telomere attrition, which can lead to alterations in chromatin compaction/gene expression. The study results may potentially deepen understanding regarding the biological processes underlying PN symptoms and lead to improved strategies for symptom management in women with BC.