Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors

Abstract

Chromothripsis and chromoanasynthesis are catastrophic events leading to clustered genomic rearrangements. Whole-genome sequencing revealed frequent chromothripsis or chromoanasynthesis (n= 16/26) in brain tumors developing in mice deficient for factors involved in homologous-recombination-repair or nonhomologous-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 tumors with complex genomic rearrangements.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.The copyright holder for this preprint . http://dx.doi.org/10.1101/314518 doi: bioRxiv preprint first posted online May. 4, 2018; 3 Chromothripsis and chromoanasynthesis are two forms of genomic instability that lead to complex genomic rearrangements affecting one or very few chromosomes [1][2][3] . These two types of catastrophic events play a role in numerous tumor entities as well as in some congenital diseases 3,4 . The first form, chromothripsis, is characterized by the simultaneous occurrence of tens to hundreds of clustered DNA double-strand breaks 1,5 . The DNA fragments resulting from this shattering event are re-ligated by error-prone repair processes, with some of the fragments being lost. The outcome is a highly rearranged derivative chromosome, with oscillations between two or three copy-number states 6 . Conversely, the local rearrangements arising from chromoanasynthesis exhibit altered copy number due to serial microhomologymediated template switching during DNA replication 2 . Resynthesis of fragments from one chromatid and frequent insertions of short sequences between the rearrangement junctions are associated with copy number gains and retention of heterozygosity 2 .The availability of murine tumor models recapitulating these phenomena would substantially facilitate the investigation of the mechanistic aspects underlying chromothripsis and chromoanasynthesis. We showed previously the role of constitutive and somatic DNA repair defects in catastrophic genomic events in the context of TP53 and ATM mutations 5,7 . Further factors essential to the biochemical and signaling context of occurrence of these catastrophic events remain to be identified, and the role of repair processes in chromothripsis and chromoanasynthesis needs to be better defined.Homologous recombination repair (HR) and canonical non-homologous endjoining (cNHEJ) represent the two major repair processes for DNA double-strand breaks in mammalian cells. Conditional inactivation of key repair factors of either of these t...

Repair of G1 induced DNA double-strand breaks in S-G2/M by alternative NHEJ

“…Because more advanced tumor cells are generally highly proliferative and often harbor deficiencies in DNA damage response and repair pathways, based on our results presented in this study, we suggest that the accumulation of chromosomal rearrangements in these cells might be fueled by alt-NHEJ in S-G2/M and that these events would give rise to tumors containing complex karyotypes. In support of this, loss of LIG4 or XRCC4 in the context of p53-deficiency was recently reported to be associated with a more frequent occurrence of complex genome rearrangements in glioblastoma 49 .…”

Higher prevalence of homologous recombination deficiency in tumors from African Americans versus European Americans

“…Lung tumors from AAs have more frequent complex structural variants. The observed deficiencies in DNA damage repair related to GI in LUSC prompted us to chart the landscape of complex structural variants recently reported to be related to HRD 16 . We studied CHTP, which was first described as a catastrophic event that leads to chromosome shattering and tens to hundreds of simultaneously acquired oscillatory copy-number aberrations on one chromosome 17,18 .…”

Impact of extracellular matrix stiffness on genomic heterogeneity in MYCN-amplified neuroblastoma cell line

“…Moreover, Rac GTPase has been shown to regulate 3D invasion in NB lacking MYCN ampli cation [81]. It is plausible that ALK-mutated cells respond to ECM changes through epigenetic alterations, genetic mutations or post-translational modi cations undetected by the techniques we employed [53,[82][83][84]. Various mechanisms of ECM's in uence on genomic heterogeneity have also been outlined.…”