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 ZapatkaPeter J. McKinnon, Frederick W. Alt, Peter Lichter, Aurélie Ernst

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

57 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Artikelnummer4760
TijdschriftNature Communications
Volume9
Nummer van het tijdschrift1
DOI's
StatusGepubliceerd - 1 dec. 2018
Extern gepubliceerdJa

Vingerafdruk

Duik in de onderzoeksthema's van 'Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors'. Samen vormen ze een unieke vingerafdruk.

Citeer dit