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

Alicia K. Smith, Karen N. Conneely, Thaddeus Wesley Warren Pace, Donna Mister, Jennifer C. Felger, Varun Kilaru, Mary J. Akel, Paula M. Vertino, Andrew H. Miller, Mylin A. Torres

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)227-236
Number of pages10
JournalBrain, Behavior, and Immunity
Volume38
DOIs
StatePublished - 2014

Fingerprint

Epigenomics
Fatigue
Methylation
Breast Neoplasms
Inflammation
Drug Therapy
Receptors, Tumor Necrosis Factor, Type II
DNA Methylation
Radiotherapy
Interleukin-6
Blood Cells
Breast
Biomarkers
Segmental Mastectomy
DNA
Exons
Therapeutics
Genome
Neoplasms
Proteins

Keywords

  • Breast cancer treatment
  • Epigenetics
  • Fatigue
  • Inflammation

ASJC Scopus subject areas

  • Immunology
  • Behavioral Neuroscience
  • Endocrine and Autonomic Systems
  • Medicine(all)

Cite this

Epigenetic changes associated with inflammation in breast cancer patients treated with chemotherapy. / Smith, Alicia K.; Conneely, Karen N.; Pace, Thaddeus Wesley Warren; Mister, Donna; Felger, Jennifer C.; Kilaru, Varun; Akel, Mary J.; Vertino, Paula M.; Miller, Andrew H.; Torres, Mylin A.

In: Brain, Behavior, and Immunity, Vol. 38, 2014, p. 227-236.

Research output: Contribution to journalArticle

Smith, AK, Conneely, KN, Pace, TWW, Mister, D, Felger, JC, Kilaru, V, Akel, MJ, Vertino, PM, Miller, AH & Torres, MA 2014, 'Epigenetic changes associated with inflammation in breast cancer patients treated with chemotherapy', Brain, Behavior, and Immunity, vol. 38, pp. 227-236. https://doi.org/10.1016/j.bbi.2014.02.010
Smith, Alicia K. ; Conneely, Karen N. ; Pace, Thaddeus Wesley Warren ; Mister, Donna ; Felger, Jennifer C. ; Kilaru, Varun ; Akel, Mary J. ; Vertino, Paula M. ; Miller, Andrew H. ; Torres, Mylin A. / Epigenetic changes associated with inflammation in breast cancer patients treated with chemotherapy. In: Brain, Behavior, and Immunity. 2014 ; Vol. 38. pp. 227-236.
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AU - Pace, Thaddeus Wesley Warren

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AU - Felger, Jennifer C.

AU - Kilaru, Varun

AU - Akel, Mary J.

AU - Vertino, Paula M.

AU - Miller, Andrew H.

AU - Torres, Mylin A.

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AB - 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.

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