Open AccessDefective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors
Author(s) -
Manasi Ratnaparkhe,
John Wong,
PeiChi Wei,
Mario Hlevnjak,
Thorsten Kolb,
Milena Simović,
Daniel Haag,
Yashna Paul,
Frauke Devens,
Paul A. Northcott,
David Jones,
Marcel Kool,
Anna Jauch,
Agata Pastorczak,
Wojciech Młynarski,
Andrey Korshunov,
Rajiv Kumar,
Susanna M. Downing,
Stefan M. Pfister,
Marc Zapatka,
Peter J. McKin,
Frederick W. Alt,
Peter Lichter,
Aurélie Ernst
Publication year - 2018
Publication title -
nature communications
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.559
H-Index - 365
ISSN - 2041-1723
DOI - 10.1038/s41467-018-06925-4
Subject(s) - dna damage , dna repair , genome instability , dna , biology , cancer research , genetics , computational biology
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.