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Breast cancer Epigenetic warning for fibrosis risk identified during radiotherapy
Radiation therapy is still an elementary component of therapy in many cancers. However, this sometimes brings with it significant side effects. A dreadful late effect of radiotherapy is so-called radiation fibrosis. Now scientists of the German Cancer Research Center (DKFZ) and the University Hospital Mannheim have identified an epigenetic feature that indicates an increased risk of radiation fibrosis.
According to the DKFZ, radiation fibrosis is a frequent long-term consequence of radiotherapy. However, the scientists of the DKFZ and the Mannheim University Hospital were able to determine an epigenetic pattern in breast cancer patients "which, depending on its severity, indicates an increased risk of fibrosis," according to the DKFZ. Based on the sample, the risk of fibrosis can be estimated even before the start of radiotherapy, and with the appropriate active ingredients, it may also be possible to interrupt the process leading to the development of radiation fibrosis, the researchers report.
The risk of fibrosis can be estimated using an epigenetic pattern even before the start of radiotherapy. (Image: bittedankeschön / fotolia.com) Radiation fibrosis often long-term consequence of radiotherapy
In around two-thirds of all cancer patients, radiotherapy, according to the DKFZ, is one of the current treatment regimens. In particular, since doctors are able to steer the rays more and more precisely to the tumors, they are used even more. "Most patients tolerate the therapy well, but it can also lead to side effects," the researchers report. "Radiation fibrosis, which often severely affects patients' quality of life, is particularly problematic." Radiation fibrosis can arise, for example, after irradiation of tumors of the bladder or lungs, but breast cancer also affects up to five percent of patients Notice from the DKFZ. Fibrosis is characterized by "scarred reshuffling, in which the healthy tissue is replaced by less elastic connective tissue and thus hardened and limited in its function," explain the experts. Radiation fibrosis often occurs only as a late sequel several months to years after the therapy. This is particularly critical because it does not regress in contrast to temporary side effects such as fatigue or diarrhea.
Identification of epigenetic aberrations
"If doctors already knew at the diagnosis which patients have a particularly high risk of fibrosis, one could reduce the radiation dose or switch to other therapies," emphasizes Odilia Popanda from the DKFZ. An epigenetic feature could warn of high fibrosis sensitivity as a biomarker in the future, even before the start of radiation therapy, the researchers report. However, the few genetic markers heretofore known to have a particular susceptibility to fibrosis do not provide a satisfactory explanation for the onset of the disease. Therefore, researchers addressed the question of whether certain epigenetic features could deregulate the cellular signaling pathways that govern the development of fibrosis. "We were particularly interested in whether we could identify epigenetic deviations that point to a high risk of fibrosis even before radiotherapy is initiated," emphasizes Odilia Popanda.
Connective tissue cells from 75 breast cancer patients analyzed
In their study, the researchers isolated connective tissue cells from skin biopsies from 75 breast cancer patients who had been removed before the radiation. Based on the genome of the cells, the researchers analyzed genome wide methylation pattern of DNA, so the announcement of the DKFZ. They found a particularly clear correlation with the later occurrence of radiation fibrosis for the genetic enhancer element of the enzyme DGKA (diacyl-glycerol kinase alpha). For example, patients whose DGKA (enhancer) enhancer was only poorly methylated were particularly susceptible to fibrosis, the researchers report. "If this gene amplifier is only poorly methylated, certain transcription factors can dock there, the DGKA gene is read more frequently, which ultimately leads to an activation of the connective tissue cells," explains Christof Weigel, first author of the study.
Interruption of the process possible?
In a further step, the researchers found that skin cell culture treatment with a drug that specifically inhibits the enzyme DGKA results in weaker activation of the connective tissue cells, which is considered a critical first step in fibrosis. Not only have researchers been able to identify a marker for the risk of fibrosis, but they may also have discovered a way to prevent the burdening side effects. "With DGKA inhibitors, it is already possible to inhibit the growth of cancer cells and successfully fight inflammatory conditions, and possibly they can also be used to prevent radiation fibroses," the DKFZ concludes. (Fp)