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

Manasi Ratnaparkhe, John K. L. Wong, Pei-Chi Wei, Mario Hlevnjak, Thorsten Kolb, Milena Simovic, Daniel Haag, Yashna Paul, Frauke Devens, Paul Northcott, David T. W. Jones, Marcel Kool, Anna Jauch, Agata Pastorczak, Wojciech Mlynarski, Andrey Korshunov, Rajiv Kumar, Susanna M. Downing, Stefan M. Pfister, Marc Zapatka, Peter J. McKinnon, Frederick W. Alt, Peter Lichter and Aurélie Ernst ()
Additional contact information
Manasi Ratnaparkhe: Heidelberg University Germany
John K. L. Wong: German Cancer Research Center (DKFZ)
Pei-Chi Wei: Harvard Medical School
Mario Hlevnjak: German Cancer Research Center (DKFZ)
Thorsten Kolb: German Cancer Research Center (DKFZ)
Milena Simovic: Heidelberg University Germany
Daniel Haag: Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Yashna Paul: German Cancer Research Center (DKFZ)
Frauke Devens: German Cancer Research Center (DKFZ)
Paul Northcott: German Cancer Research Center (DKFZ)
David T. W. Jones: Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Marcel Kool: Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Anna Jauch: University of Heidelberg
Agata Pastorczak: Medical University of Lodz
Wojciech Mlynarski: Medical University of Lodz
Andrey Korshunov: Heidelberg University Hospital and German Cancer Consortium (DKTK)
Rajiv Kumar: German Cancer Research Center
Susanna M. Downing: St. Jude Children’s Research Hospital
Stefan M. Pfister: Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ)
Marc Zapatka: German Cancer Research Center (DKFZ)
Peter J. McKinnon: St. Jude Children’s Research Hospital
Frederick W. Alt: Harvard Medical School
Peter Lichter: German Cancer Research Center (DKFZ)
Aurélie Ernst: German Cancer Research Center (DKFZ)

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06925-4

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