title: 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 6months 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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 101 Woodruff Circle, Suite 4000, Atlanta, GA 30322, United States; Winship Cancer Institute, Emory University, 1365 Clifton Rd. NE, Atlanta, GA 30322, United States. Electronic address: alicia.smith@emory.edu.
authors.forename: Alicia K
authors.initials: AK
authors.lastname: Smith
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Whitehead Biomedical Research Building, 615 Michael Street, Suite 301, Atlanta, GA 30322, United States. Electronic address: kconnee@emory.edu.
authors.forename: Karen N
authors.initials: KN
authors.lastname: Conneely
authors.affiliation: College of Nursing & College of Medicine (Department of Psychiatry), University of Arizona, 1305 N. Martin Ave, Tucson, AZ 85721, Untied States. Electronic address: twwpace@email.arizona.edu.
authors.forename: Thaddeus W W
authors.initials: TW
authors.lastname: Pace
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine, 1365 Clifton Rd. NE, Atlanta, GA 30322, United States. Electronic address: dmister@emory.edu.
authors.forename: Donna
authors.initials: D
authors.lastname: Mister
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 101 Woodruff Circle, Suite 4000, Atlanta, GA 30322, United States. Electronic address: jfelger@emory.edu.
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Felger
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 101 Woodruff Circle, Suite 4000, Atlanta, GA 30322, United States. Electronic address: vkilaru@emory.edu.
authors.forename: Varun
authors.initials: V
authors.lastname: Kilaru
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 101 Woodruff Circle, Suite 4000, Atlanta, GA 30322, United States. Electronic address: makel@emory.edu.
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Akel
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine, 1365 Clifton Rd. NE, Atlanta, GA 30322, United States; Winship Cancer Institute, Emory University, 1365 Clifton Rd. NE, Atlanta, GA 30322, United States. Electronic address: pvertin@emory.edu.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Vertino
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, 101 Woodruff Circle, Suite 4000, Atlanta, GA 30322, United States; Winship Cancer Institute, Emory University, 1365 Clifton Rd. NE, Atlanta, GA 30322, United States. Electronic address: amill02@emory.edu.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Miller
authors.affiliation: Department of Radiation Oncology, Emory University School of Medicine, 1365 Clifton Rd. NE, Atlanta, GA 30322, United States; Winship Cancer Institute, Emory University, 1365 Clifton Rd. NE, Atlanta, GA 30322, United States. Electronic address: matorre@emory.edu.
authors.forename: Mylin A
authors.initials: MA
authors.lastname: Torres
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005221:Fatigue / Q000276:immunology*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000235:genetics; D008875:Middle Aged
chemical_list: D000970:Antineoplastic Agents
keywords: Breast cancer treatment; Epigenetics; Fatigue; Inflammation