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Researchers have found that medulloblastomas and high-grade gliomas, two types of brain tumors, often exhibit frequent, complex rearrangements of the genome as a result of malfunctioning DNA repair.
Scientists at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) investigated the cause of chromothripsis, one of two "catastrophic genomic events" that cause genomic instability and are implicated in the development of cancer. In chromothripsis, tens to hundreds of clustered DNA double-strand breaks happen simultaneously. The ensuing DNA fragments are joined together again through error-prone repair processes in which some fragments are lost, resulting in a heavily rearranged derivative chromosome that oscillates between two or three copy number states.
In their study published this week in Nature Communications, the researchers sought to understand the role that DNA repair processes play in these catastrophic events.
There are two major repair processes for double-strand breaks of DNA in mammalian cells: homologous-recombination repair and canonical non-homologous end-joining. Previous research has shown that in mouse models deficient in p53—a gene which codes for a protein that regulates tumor suppression—conditional inactivation of factors essential to either of these two repair processes results in medulloblastomas or high-grade gliomas. The DKFZ investigators have now revealed the means by which inactivation of one or more of these repair factors leads to these cancers: through frequent, complex rearrangements of the genome.
Using whole-genome sequencing, the researchers found that of 26 mouse brain tumors deficient in factors needed for homologous-recombination repair or canonical non-homologous end-joining, 16 exhibited frequent, complex genomic rearrangements. Catastrophic events were strongly associated with amplification of Myc or Mycn, oncogenes that can cause cancer when mutated, resulting in increased DNA damage and inefficient cell death.
Comparing the mouse tumors with 68 human medulloblastomas and 32 glioblastomas demonstrated that in humans, chromothripsis was associated with DNA repair deficiencies and increased MYC or MYCN proteins.
"If the DNA repair is defective and Myc nevertheless stimulates the division of these damaged cells, the risk of chaos in the genome is particularly high," explained the study's senior author, Dr. Aurélie Ernst, Team Leader of the Genome Instability and Cell Turnover in Cancer laboratory at DFKZ.
"The chromosome chaos caused by repair defects is frightening at first sight," commented Dr. Ernst. "However, there are ways to specifically combat cancer cells harboring such defects: we can use drugs to switch off additionally another important DNA repair system. This leads to so much genetic damage that the cell is unable to survive. Healthy cells, on the other hand, which have all their repair systems, don't mind these drugs."
Dr. Ernst already has a potential class of drugs in mind: "If the analysis of a patient's tumor genome reveals evidence of chromothripsis, treatment with PARP inhibitors could be a new therapeutic option in the future. Of course, this has to be confirmed in preclinical and clinical tests."
For More Information
Ratnaparkhe M, Wong JKL, Wei PC, et al (2018). Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors. Nat Commun, 9:4760. DOI:10.1038/s41467-018-06925-4