Abstract

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.

Details

Title
Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors
Author
Ratnaparkhe, Manasi 1 ; Wong, John K L 2 ; Pei-Chi, Wei 3 ; Hlevnjak, Mario 2 ; Kolb, Thorsten 2 ; Simovic, Milena 1 ; Haag, Daniel 4 ; Yashna, Paul 2 ; Devens, Frauke 2 ; Northcott, Paul 5 ; Jones, David T W 4 ; Kool, Marcel 4 ; Jauch, Anna 6 ; Pastorczak, Agata 7 ; Mlynarski, Wojciech 7 ; Korshunov, Andrey 8 ; Kumar, Rajiv 9   VIAFID ORCID Logo  ; Downing, Susanna M 10 ; Pfister, Stefan M 4 ; Zapatka, Marc 2 ; McKinnon, Peter J 10 ; Alt, Frederick W 3 ; Lichter, Peter 2 ; Ernst, Aurélie 2 

1  Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ); Faculty of Biosciences, Heidelberg University Germany, Heidelberg, Germany 
2  Division of Molecular Genetics, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany 
3  Boston Children’s Hospital, Howard Hughes Medical Institute and Department of Genetics, Harvard Medical School, Boston, MA, USA 
4  Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany 
5  Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, United States 
6  Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany 
7  Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland 
8  Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Department of Neuropathology, Heidelberg University Hospital and German Cancer Consortium (DKTK), Heidelberg, Germany 
9  Division of Molecular Genetic Epidemiology; German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center, Heidelberg, Germany 
10  Department of Genetics, St. Jude Children’s Research Hospital, Memphis, TN, USA 
Pages
1-13
Publication year
2018
Publication date
Nov 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-018-06925-4
ProQuest document ID
2132241860
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.