What cell repair reveals about cancer recurrence
Bild: Moixó Studio - stock.adobe.com / AG Löbrich
Researchers at Technische Universität Darmstadt and the University Medical Centre of Johannes Gutenberg University Mainz have investigated how effectively cells from people who had cancer in childhood can repair minor radiation-induced genetic damage. The study found that repair was markedly more efficient in people who had cancer as children than in cancer-free individuals – a difference that did not emerge in the case of more extensive damage. The new insights into the mechanism responsible for this repair also offer clues as 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 (PNAS).
For the study, conducted as part of the collaborative project ISIBELa (Intrinsic Radiosensitivity: Identification of Biological and Epidemiological Long-term Effects), funded by Germany's Federal Ministry of Education and Research (BMBF), the researchers first used X-rays to induce genetic damage of varying severity in skin cells, then tracked the cells' repair process as it got under way and assessed the damage that remained. The study involved 204 adult cell donors: cancer-free individuals as well as adult survivors of childhood cancer, half of whom had gone on to develop a further cancer unrelated to the first tumour. The childhood cancer 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 of the study was to establish whether the two groups differed in how effectively such genetic damage is repaired, and whether this might explain why some people develop cancer early in life or even go on to develop several cancers in succession.
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 passed on to the research group of Professor 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). In this way, the researchers induced DNA double-strand breaks – damage to the genetic material that the cells then go on to repair, where possible. One day after irradiation, the remaining radiation-induced genetic damage was assessed microscopically in individual cells to determine each study participant's individual 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.
After irradiation with the higher doses of 10 and 100 milligray, the repair efficiency of the genetic damage was comparable between the former childhood cancer patients and the cancer-free donors. Surprisingly, a difference emerged in the case of the more minor damage caused by the lowest dose, 2.5 milligray: whereas repair proceeded inefficiently in the cancer-free donors, consistent with earlier observations, the cells of former childhood cancer patients repaired this 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 tumour treatment – influence the repair of genetic damage. The main mechanisms responsible for repairing such damage are probably unaffected. Instead, the changes may selectively modulate cellular systems or signalling pathways that activate repair mechanisms in situations where they would remain inactive in healthy individuals. The repair mechanisms are, in a sense, “overzealous”.
Earlier research has shown that, in people without cancer, the repair of genetic damage can be triggered by oxygen radicals. The present findings suggest that changes in the so-called redox system – which, among other things, manages oxygen radicals within the cell – are responsible for the fact that survivors of childhood cancer also repair minor cellular damage. This is not automatically an advantage, however, since every repair process carries the risk of errors or mutations that may, in certain circumstances, contribute to the development of new cancers. For an organism, it can therefore be considerably safer to replace cells with damaged genetic material rather than repair them. Repair only becomes necessary once numerous instances of damage occur simultaneously. Further studies are now planned to clarify whether, and in what way, such changes in the repair mechanism have contributed to the development of tumours in childhood or of subsequent cancers.
Background
The study, “Repair of DNA double-strand breaks after low radiation doses in childhood cancer survivors and matched cancer-free individuals,” was carried out as part of the collaborative project ISIBELa (Intrinsic Radiosensitivity: Identification of Biological and Epidemiological Long-term Effects, 2015–2021, funding reference: 02NUK042A-D), funded by the Federal Ministry of Education and Research. Researchers from the Rhine-Main Universities (RMU) TU Darmstadt and Johannes Gutenberg University Mainz, the Mainz University Medical Centre, the German Childhood Cancer Registry (Mainz) and the Leibniz Institute for Prevention Research and Epidemiology – BIPS (Bremen) contributed to the study.
