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 tumors with complex genomic rearrangements.

Recent developments in sequencing technologies led to the discovery of a novel form of genomic instability, termed chromothripsis. This catastrophic genomic event, involved in tumorigenesis, is characterized by tens to hundreds of simultaneously acquired locally clustered rearrangements on one chromosome. We hypothesized that leukemias developing in individuals with Ataxia Telangiectasia, who are born with two mutated copies of the ATM gene, an essential guardian of genome stability, would show a higher prevalence of chromothripsis due to the associated defect in DNA double-strand break repair. Using whole-genome sequencing, fluorescence in situ hybridization and RNA sequencing, we characterized the genomic landscape of Acute Lymphoblastic Leukemia (ALL) arising in patients with Ataxia Telangiectasia. We detected a high frequency of chromothriptic events in these tumors, specifically on acrocentric chromosomes, as compared with tumors from individuals with other types of DNA repair syndromes (27 cases total, 10 with Ataxia Telangiectasia). Our data suggest that the genomic landscape of Ataxia Telangiectasia ALL is clearly distinct from that of sporadic ALL. Mechanistically, short telomeres and compromised DNA damage response in cells of Ataxia Telangiectasia patients may be linked with frequent chromothripsis. Furthermore, we show that ATM loss is associated with increased chromothripsis prevalence in additional tumor entities.

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...