A study of how cells repair radiation-induced genetic damage offers clues to why some people develop cancer early in life or more than once. The findings were recently published in the journal Proceedings of the National Academy of Sciences.
The study was conducted as part of the collaborative project ISIBELa (Intrinsic Radiosensitivity: Identification of Biological and Epidemiological Long-term Effects). Researchers used X-rays to induce genetic damage of varying severity in skin cells, then tracked the cells’ repair process and assessed the damage that remained.
The study involved 204 adult cell donors: cancer-free individuals and survivors of childhood cancer, half of whom had gone on to develop another cancer unrelated to the first tumor. The survivors were recruited with the help of the German Childhood Cancer Registry (Mainz) and the Leibniz Institute for Prevention Research and Epidemiology—BIPS (Bremen).
The aim was to establish whether the groups differed in how effectively they repaired genetic damage and whether this might explain why some people develop cancer early in life or go on to develop several cancers in succession.
Tracking repair in irradiated skin cells
For the analysis, connective tissue cells (fibroblasts) were isolated from small skin samples taken from all participants and processed into a biobank at the radio-oncology research laboratory of Mainz University Medical Centre. The cells were then sent to the research group of Markus Löbrich at TU Darmstadt, where they were cultured and irradiated with very low doses of X-rays (2.5, 5, 10, 25 and 100 milligray).
The researchers induced DNA double-strand breaks, damage to genetic material that cells then repair where possible. One day after irradiation, the remaining radiation-induced damage was assessed microscopically in individual cells to determine each participant’s repair efficiency. The statistical analysis was carried out in collaboration with the Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI) at Mainz University Medical Centre.
Survivors repaired damage at the lowest dose
After irradiation with the higher doses of 10 and 100 milligray, repair efficiency was comparable between childhood cancer survivors and cancer-free donors. A difference emerged, however, with the less extensive damage caused by the lowest dose, 2.5 milligray: Repair was inefficient in the cancer-free donors, consistent with earlier observations, but the survivors’ cells repaired the damage with an efficiency comparable to that seen after the higher doses.
These findings suggest that (epi)genetic changes in survivors of childhood cancer—whether inherited or caused by earlier tumor treatment—influence the repair of genetic damage. The main mechanisms responsible for repairing such damage are probably unaffected. Instead, the changes may selectively affect cellular systems or signaling pathways that activate repair mechanisms in situations where they would remain inactive in healthy individuals. The repair mechanisms are, in a sense, “overzealous.”
Overzealous repair may carry risks
Earlier research has shown that oxygen radicals can trigger the repair of genetic damage in people without cancer. The findings suggest that changes in the so-called redox system—which, among other things, manages oxygen radicals within the cell—cause survivors of childhood cancer to repair minor cellular damage as well.
This is not automatically an advantage: Every repair process carries the risk of errors or mutations that may, in certain circumstances, contribute to new cancers. For an organism, it can therefore be considerably safer to replace cells with damaged genetic material rather than repair them. Repair becomes necessary only when numerous instances of damage occur simultaneously. Further studies are planned to clarify whether, and in what way, such changes in the repair mechanism have contributed to the development of tumors in childhood or subsequent cancers.