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Chemotherapy-related DNA changes linked to long-term fatigue in breast cancer
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Long-term epigenetic changes associated with chemotherapy may account in part for inflammation and subsequent fatigue in patients with breast cancer, according to study results findings.
Researchers from Winship Cancer Institute of Emory University evaluated DNA samples from 61 women with stage I to stage IIIA breast cancer who had undergone partial mastectomy, with or without chemotherapy. The DNA was collected from the patients’ peripheral blood mononuclear cells before they underwent breast radiation therapy.
The investigators evaluated DNA methylation at more than 485,000 CpG sites across the genome, as well as fatigue and inflammatory markers linked to fatigue.
The researchers found significantly reduced methylation at eight CpG sites (P<1.03 x 10-7). Lower methylation at each CpG location was linked to increased concentrations of two inflammatory signaling proteins, plasma soluble tumor necrosis factor receptor 2 (sTNFR2) and interleukin (IL) 6, which are associated with fatigue in cancer survivors. Lower methylation moderated the relationship between chemotherapy and these inflammatory biomarkers after adjusting for several clinical and treatment factors.
These assessments of DNA methylation, inflammatory biomarkers and fatigue were repeated 6 months after breast radiation in a subset of 39 patients.
This evaluation revealed that there was still reduced methylation in four of the eight identified CpG sites in the chemotherapy patients compared with the non-chemotherapy patients. There was some diminishment of these changes, however, indicating that this effect may be reversible. The decreased methylation seen in these four CpG sites had a continued association with increases either in sTNFR2 or IL-6, but not with fatigue.
According to study investigator Andrew Miller, MD, director of psychiatric oncology at the Winship Cancer Institute, chemotherapy may play a direct role in changes to methylation status in blood cells; alternately, changes in methylation may be a result of chemotherapy-related tissue injury and subsequent inflammation.
“It may be something about the intensity or the repetitive nature of chemotherapy that makes it qualitatively different from acute inflammation,” Miller said in a press release. “The more we know about this imprinting process, the better chance we have of getting to new therapies for chronic treatment-related problems, such as fatigue, in breast cancer survivors
Disclosure: The researchers report no relevant financial disclosures.
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