Epigenetic imprint of chemotherapy linked to inflammation in breast cancer survivors

Chemotherapy, one of the major treatments for breast cancer, can leave a long-lasting epigenetic imprint in the DNA of the blood cells of breast cancer patients, according to new research. That imprint is associated with biological signs of inflammation up to 6 months after the completion of treatment. Inflammation in turn is believed to cause symptoms such as fatigue.

"Chemotherapy is a life-saving intervention, but for some women it comes at a cost," said Mylin Torres, MD, assistant professor of radiation oncology at Emory University School of Medicine and Winship Cancer Institute in Atlanta, Georgia. "These results are the first to suggest a biological mechanism by which treatment-related side effects can persist long after treatment completion in women with breast cancer."

That achy, tired feeling that comes from the flu is caused by inflammation, the body's natural response to infection or a wound—but it usually disappears once an illness is over. In patients being treated for cancer, fatigue has also been linked to inflammation and up to 30% of breast cancer survivors experience persistent fatigue long after treatment has ended.

To investigate the biology behind persistent cancer-related inflammation, Torres teamed up with Andrew Miller, MD, professor of psychiatry and behavioral sciences and director of psychiatric oncology at Winship Cancer Institute. Other coauthors brought specialties in psychiatry and behavioral sciences, and in human genetics.

In the current study, published in Brain, Behavior and Immunity (2014; doi:10.1016/j.bbi.2014.02.010), all the women went through partial mastectomy surgery. Some received varying forms of chemotherapy, and all received radiation at the end.

They found that women who had been treated with chemotherapy exhibited changes in the methylation of the DNA in their white blood cells. Some of these changes were still present 6 months after radiation.

Methylation is an epigenetic alteration in DNA, which does not change the A/C/G/T "letter" information in the DNA but does change how that information is read by the cell, influencing whether a gene is turned on or off.

The researchers scanned hundreds of thousands of potential sites of methylation; only eight sites were reliably altered in women who received chemotherapy, and changes at half of those sites were visible 6 months later.

Many chemotherapeutic agents are effective precisely because they damage DNA in cancer cells. Although it was well known that chemotherapy induces epigenetic changes in cancer cells, this is the first study to identify epigenetic changes induced by chemotherapy for breast cancer in noncancerous cells of the blood.

The authors hypothesize that chemotherapy may directly alter methylation status in the blood cells, or it may be a result of the inflammatory response to chemotherapy-related tissue injury.

"It may be something about the intensity or the repetitive nature of chemotherapy that makes it qualitatively different from acute inflammation," Miller said. "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."

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