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

• Published in: Nature communications Vol. 9; no. 1; pp. 4760 - 13
• Main Authors: Ratnaparkhe, Manasi, Wong, John K. L., Wei, Pei-Chi, Hlevnjak, Mario, Kolb, Thorsten, Simovic, Milena, Haag, Daniel, Paul, Yashna, Devens, Frauke, Northcott, Paul, Jones, David T. W., Kool, Marcel, Jauch, Anna, Pastorczak, Agata, Mlynarski, Wojciech, Korshunov, Andrey, Kumar, Rajiv, Downing, Susanna M., Pfister, Stefan M., Zapatka, Marc, McKinnon, Peter J., Alt, Frederick W., Lichter, Peter, Ernst, Aurélie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12.11.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/106; 13/51; 14/1; 14/32; 14/34; 14/63; 38/23; 38/77; 49; 59; 631/337/1427; 631/67/68; 631/67/70; 64; 64/60; 82/80; 96/109; Animals; Apoptosis; Apoptosis - genetics; Brain; Brain Neoplasms - genetics; Brain Neoplasms - pathology; Brain tumors; Catastrophic events; Cell Line, Tumor; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - genetics; DNA End-Joining Repair - genetics; DNA repair; DNA Repair - genetics; DNA-Binding Proteins - metabolism; Gene Amplification; Gene Rearrangement - genetics; Gene sequencing; Genome; Genomes; Homologous recombination; Homologous Recombination - genetics; Homology; Humanities and Social Sciences; Humans; Karyotyping; Mice; multidisciplinary; N-Myc Proto-Oncogene Protein - genetics; Neural Stem Cells - metabolism; Neural Stem Cells - pathology; Proto-Oncogene Proteins c-myc - genetics; Repair; Science; Science (multidisciplinary); Tumor Suppressor Protein p53 - metabolism; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-06925-4

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. Chromothripsis and chromoanasynthesis lead to locally clustered rearrangements affecting one or a few chromosomes, but their impact on cancer development and progression is unclear. Here the authors analyse the role of DNA repair factors in brain tumors by whole-genome sequencing of tumors from mouse models of medulloblastoma or high grade gliomas.