Epigenetic changes associated with inflammation in breast cancer patients treated with chemotherapy

Abstract

Inflammation has been associated with fatigue during and after various types of breast cancer treatments. We examined whether prior chemotherapy was associated with DNA methylation patterns that could explain persisting inflammation and/or fatigue in women treated for breast cancer. Prior to breast radiation therapy, DNA was extracted from peripheral blood mononuclear cells (PBMCs) of 61 Stage 0-IIIA breast cancer patients who had received partial mastectomy with or without chemotherapy. DNA methylation was assessed at >485,000 CpG sites across the genome along with fatigue and plasma inflammatory markers previously associated with fatigue. Compared to non-chemotherapy-treated, women who had received chemotherapy exhibited significantly decreased methylation at eight CpG sites (p < 1.03 × 10−7) including four in exon 11 of transmembrane protein 49 (TMEM49), which demonstrated the largest decreases in methylation. Lower methylation at each identified CpG site was associated with increased plasma soluble tumor necrosis factor receptor 2 (sTNFR2) and interleukin (IL)-6 and mediated the relationship between chemotherapy and increases in these inflammatory biomarkers adjusting for multiple clinical and treatment characteristics. sTNFR2, but not CpG methylation status, was correlated with fatigue. Six months after breast radiation therapy, DNA methylation, inflammatory biomarkers and fatigue assessments were repeated in a subset of subjects (N = 39). Reduced methylation in 4 of the 8 identified CpG sites was still observed in chemotherapy versus non-chemotherapy-treated patients, albeit with some decay indicating the dynamic and potentially reversible nature of the changes. Reduced methylation in these 4 CpG sites also continued to correlate with either increased sTNFR2 or IL-6, but not fatigue. In conclusion, prior chemotherapy treatment was associated with decreased methylation of CpG sites in DNA from PBMCs of breast cancer patients, which correlated with increased inflammatory markers prior to and 6 months after radiation therapy. Persisting epigenetic changes secondary to chemotherapy may be one factor that contributes to inflammation and its consequences including cancer-related fatigue in vulnerable breast cancer patients.

Polymorphisms in Cytokine Genes Are Associated With Higher Levels of Fatigue and Lower Levels of Energy in Women After Breast Cancer Surgery

“…In several studies,(21–24) genetic and epigenetic mechanisms involved in inflammation were associated with fatigue in oncology patients. Only one study was found that reported on associations between polymorphisms in cytokine genes and decrements in energy in oncology patients undergoing radiation therapy and their family caregivers.…”

DNA cytosine hydroxymethylation levels are distinct among non-overlapping classes of peripheral blood leukocytes

“…One implicit assumption is that genetic and epigenetic reprogramming caused by disease states in other tissues are systemically reflected in blood-borne leukocytes. There are numerous published studies examining the response of genome-methylation in whole blood leukocytes to diseases and disease progression (Javierre et al, 2010; Wang et al, 2010; Weiss et al, 2011; Saied et al, 2012; Schroeder et al, 2012; Smith et al, 2012, 2014; Sun et al, 2013; Xu et al, 2013; Almen et al, 2014). However, the genome-wide methylation data from these studies comprises the epigenomic information of several major leukocyte cell types combined as a weighted average of their fractional representation in blood.…”

The influence of cancer on endocrine, immune, and behavioral stress responses

“…For example, the period immediately pre-surgery for tumor resection may be assumed to be a relatively stressful period of anticipation, however as opposed to most studies using experimental stressors, no differences in anxiety or cortisol were observed among various stages of ovarian cancer in this period (Schrepf et al, 2013). Other inherent "treatment stressor" studies (i.e., using radiation and chemotherapy) inevitably demonstrate induced inflammatory responses, do not incorporate cancer-free controls, and are beyond the scope of this review (Bower et al, 2011b;Burnette and Weichselbaum, 2013;Liu et al, 2012;Schaue et al, 2015;Smith et al, 2014). The endocrine, inflammatory, and behavioral responses following (select…”