Epigenetics and Psychoneurologic Symptoms in Women with Breast Cancer

尽管乳腺癌治疗的进步提高了存活率，但大多数患有乳腺癌(BC)的女性在治疗过程中会出现痛苦的症状，对一些人来说，这种症状会持续到生存。在患有BC的女性中，最常见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，这些症状统称为“心理神经(PN)症状”。炎症激活和表观遗传学改变与癌症的病因和各种慢性神经认知障碍有关。然而，到目前为止，还没有研究人员认为这些表观遗传过程可能与BC患者女性PN症状的病因有关。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变化与PN症状的发展和持续性的关系可以为未来开发预测标记和治疗方法提供基础知识，以解决与BC妇女的PN症状相关的表观遗传变化。 因此，这项研究的具体目的是探讨： 1.各时间点PN症状的出现频率、严重程度及症状之间的相互关系。 2.炎症水平，并量化化疗后表观遗传模式随时间变化的频率和全基因组定位。 3.炎症、表观遗传学改变与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，这项拟议的研究将前瞻性地表征75名被诊断为早期BC的妇女在5个时间点的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)、白介素1β(IL-1B)和白介素6(IL-6)的水平]以及表观遗传学变化：在接受化疗前、第四次化疗时、开始化疗后的6、12和24个月。表观遗传学的改变将通过定量检测：(1)甲基化的频率和全基因组的位置；(2)组蛋白甲基转移酶EZH2的表达，这是一种多梳蛋白，被认为是表观遗传“决定”过程的早期步骤；以及(3)端粒磨损，它可能导致染色质压缩/基因表达的变化。研究结果可能会加深对PN症状潜在的生物学过程的理解，并导致改善BC患者的症状管理策略。

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.