biostudies-literatureRatnaparkhe MFritz Thyssen StiftungNCI NIH HHSNINDS NIH HHSFritz Thyssen Stiftung (Fritz Thyssen Foundation)4760https://www.ebi.ac.uk/biostudies/studies/S-EPMC6232171biostudies-literatureUnknown9(1)Chromothripsis and chromoanasynthesis are catastrophic events leading to clustered genomic rearrangements. Whole-genome sequencing revealed frequent complex genomic rearrangements (n = 16/26) in brain tumors developing in mice deficient for factors involved in homologous-recombination-repair or non-homologous-end-joining. Catastrophic events were tightly linked to Myc/Mycn amplification, with increased DNA damage and inefficient apoptotic response already observable at early postnatal stages. Inhibition of repair processes and comparison of the mouse tumors with human medulloblastomas (n = 68) and glioblastomas (n = 32) identified chromothripsis as associated with MYC/MYCN gains and with DNA repair deficiencies, pointing towards therapeutic opportunities to target DNA repair defects in tumNature communicationsDefective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors.PMC6232171P30 CA021765P01 CA096832Az.10.17.2.030MNR01 NS037956Haag DKolb TKool MSimovic MMlynarski WZapatka MJones DTWDowning SMPfister SMWei PCRatnaparkhe MKorshunov AKumar RMcKinnon PJPaul YLichter PNorthcott PWong JKLJauch AErnst AAlt FWHlevnjak MPastorczak ADevens FfalseDefective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors.Chromothripsis and chromoanasynthesis are catastrophic events leading to clustered genomic rearrangements. Whole-genome sequencing revealed frequent complex genomic rearrangements (n = 16/26) in brain tumors developing in mice deficient for factors involved in homologous-recombination-repair or non-homologous-end-joining. Catastrophic events were tightly linked to Myc/Mycn amplification, with increased DNA damage and inefficient apoptotic response already observable at early postnatal stages. Inhibition of repair processes and comparison of the mouse tumors with human medulloblastomas (n = 68) and glioblastomas (n = 32) identified chromothripsis as associated with MYC/MYCN gains and with DNA repair deficiencies, pointing towards therapeutic opportunities to target DNA repair defects in tum2018-01-01T00:00:00Z2018 Nov2026-07-15T19:04:19.157Z2026-07-09T03:10:24.496ZS-EPMC62321713042070210.1038/s41467-018-06925-4