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Scientists from the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have now found a cause for the multiple catastrophic events of the cancer cell genetic material known in recent years: If an important system of repairing the cells' DNA failed, this promotes fragmentation and faulty assembly of the genetic material. Cancer cells with such a repair defect can now be treated with a specific group of drugs.
Only a few years ago, scientists from the German Cancer Research Center (DKFZ) described a new type of damage in the genetic material of cancer cells: in a particularly aggressive type of childhood brain tumors, they discovered a unprecedented chaos in the world. cell nucleus: individual chromosome sections were fractured at many points and reassembled incorrectly, so that whole parts were missing, while others were duplicated or embedded in an erroneous orientation. This chromosomal catastrophe was different from all known genetic abnormalities in tumors.
Scientists use the term chromothripsis to describe such a genetic catastrophe, which occurs in about twenty to thirty percent of all cancers. The trigger for this has until now been largely unknown. Aurélie Ernst and her team at the German Center for Cancer Research have now been able to demonstrate that the failure of some genetic repair systems is one of the causes of chromosomal chaos.
Many environmental influences, such as UV rays, damage the DNA. The cells have an arsenal of mechanisms in place to repair these defects. What happens if any of these repair systems goes down? The Aurelie Ernst team has tested this on genetically modified mice. In these animals, the tools used by the cell to repair broken double strands of DNA have been genetically deactivated – particularly only in neural precursor cells.
These mice developed malignant brain tumors (medulloblastomas and high grade gliomas), which exhibited chromothripsia at a high frequency. The researchers noticed that it almost always accompanied additional copies of the oncogene Myc, known to be a powerful engine of cell growth. "If the DNA repair is defective and Myc still stimulates the division of these damaged cells, the risk of chaos in the genome is particularly high," says the DKFZ researcher.
Does this link between faulty genome repair and chromosomal chaos also apply to human cancers? Aurélie Ernst and her team can confirm it for brain tumors, melanomas and breast cancer. The researchers also discovered the involvement of Myc, a cancer promoter, in human tumors.
"The chromosomal chaos caused by repair defects is scary at first glance," explains Aurélie Ernst. "However, there are ways to fight specifically against cancer cells harboring such defects: we can use drugs to disable another important DNA repair system.This causes so much genetic damage that the cell is unable to to survive, hand, which has all its repair systems, do not bother these drugs ".
PARP inhibitors are already approved drugs that block a central DNA repair system. It is also possible to develop other substances that bind to other DNA repair enzymes. "If the tumor genome analysis of a patient reveals signs of chromothripsis, treatment with PARP inhibitors might constitute a new therapeutic option in the future," says researcher DKFZ, Ernst. "Of course, this needs to be confirmed by preclinical and clinical tests.
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Material provided by German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ). Note: Content can be changed for style and length.
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