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

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-...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Article
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232171/
https://www.ncbi.nlm.nih.gov/pubmed/30420702
http://dx.doi.org/10.1038/s41467-018-06925-4
Descripción
Sumario: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.

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