Methylation: Key to chemo epigenetics

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  • Published: Mar 15, 2014
  • Author: David Bradley
  • Channels: Chemometrics & Informatics
thumbnail image: Methylation: Key to chemo epigenetics

Chemo fatigue

Repeated doses of chemotherapy to treat breast cancer comes with inevitable acute side effects, but it can also leave a long-term epigenetic imprint on the DNA of patients' blood cells. Research to scan and analyse hundreds of thousands of putative methylation sites that might be involved in this process could lead to new understanding of the effects of cancer therapy.

Chemotherapy for breast cancer comes with inevitable acute side effects, but it can also leave a long-term epigenetic imprint on the DNA of the patient's healthy white blood cells. Research to scan and analyse hundreds of thousands of putative methylation sites that might be involved in this process could lead to new understanding of the effects of cancer therapy.

Now, researchers at the Winship Cancer Institute of Emory University have uncovered news clues as to why chemotherapy can have such a lingering effect on breast cancer patients. Details are reported in the journal Brain, Behavior and Immunity online. Chemotherapy is associated with an epigenetic imprint is tied to the biological signs of inflammation for up to six months after completion of the treatment. "Almost one in three breast cancer patients suffer long-lasting after effects of chemotherapy," radiation oncologist Mylin Torres told us. "Chemotherapy is a life-saving intervention, but for some women it comes at a cost," she explains. "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."

Expressionism

To work out why this flu-like inflammation persists, Torres teamed up with Andrew Miller, Alicia Smith and geneticist Karen Conneely. In earlier work, Torres and Miller and their colleagues had identified an increase in the biomarkers of inflammation in the blood associated with chemotherapy and that the presence of these correlated with fatigue. "We had found that high fatigue levels were seen in patients no matter whether patients received chemotherapy before or after surgery," Torres explains, "indicating that the timing of chemotherapy was less important than whether you got it in the first place."

In the present work, the team looked at women who had undergone partial mastectomy surgery, some of whom also received various types of chemotherapy and all of whom received radiation therapy as the final stage of their overall treatment. The team found that women who had been treated with chemotherapy had a different methylation pattern in their white blood cells than those who did not receive chemotherapy. Some of these changes were still present six months after radiation. Methylation is an epigenetic change that can occur in DNA, but does not disrupt the sequences of bases in the DNA, so there are no "spelling mistakes", rather it as if a base has been crossed through without removing it through the addition of a methyl group. This prevents the affected gene being expressed.

Overwhelming division

The researchers scanned hundreds of thousands of potential sites of methylation. Their analysis showed that only eight of those were consistently altered in the patients who had received chemotherapy. The changes at half of those sites persisted for six months after treatment. However, the biology connecting these eight sites to inflammation remains unclear. Paradoxically, these eight sites were not in genes that are known to encode for inflammatory signalling proteins that are secreted into the blood. Nevertheless, seven of the eight have been implicated in the inflammatory process. Moreover, the presence of a methylated base was correlated with increased levels of two inflammatory signalling proteins, interleukin-6, IL-6 and sTNFR2 (a tumour necrosis factor receptor), that have been linked with chronic fatigue in breast cancer survivors.

Anticancer agents are, of course, designed to cause damage to DNA, making deliberate epigenetic changes intended to overwhelm the rapidly dividing cancer cells. Healthy tissues in the target site can also be affected but because those cells are not dividing so frequently damage does not accumulate so rapidly in healthy tissue as cancerous tissues. The toxic process does cause side effects, but this is the first finding to show that epigenetic changes in cells associated with non-cancerous tissues, i.e. white blood cells can be affected. The researchers cannot yet determine whether it is direct methylation of white blood cells that is to blame for the long-lasting after effects or whether they arise because of the inflammatory response to the 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 says. "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."

"The next step would be to validate our findings in a cohort of breast cancer patients who are assessed before and after chemotherapy in order to determine if the epigenetic changes we are seeing are indeed caused by chemotherapy treatment," Torres told SpectroscopyNow. "The ultimate intent would be to design therapeutic interventions which may reverse these epigenetic changes or identify specific chemotherapy agents which are causing the most changes and use alternative drugs in breast cancer treatment."

Related Links

Brain, Behav, Immun, 2014, online: "Epigenetic changes associated with inflammation in breast cancer 4 patients treated with chemotherapy"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

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