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

Ratnaparkhe, M.; Wong, J.; Wei, P.-C.; Hlevnjak, M.; Kolb, T.; Haag, D.; Paul, Y.; Devens, F.; Northcott, P.; Jones, D. T.; Kool, M.; Jauch, A.; Pastorczak, A.; Mlynarski, W.; Korshunov, A.; Kumar, R.; Downing, S.; Pfister, S.; Zapatka, M.; McKinnon, P. J.; Alt, F. W.; Lichter, P.; Ernst, A.

doi:10.1101/314518

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bioRxiv · 10.1101/314518

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

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Abstract

Chromothripsis and chromoanasynthesis are catastrophic events leading to clustered genomic rearrangements. Whole-genome sequencing revealed frequent chromothripsis or chromoanasynthesis (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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Ratnaparkhe, M., Wong, J., Wei, P.-C., Hlevnjak, M., Kolb, T., Haag, D., Paul, Y., Devens, F., Northcott, P., Jones, D. T., Kool, M., Jauch, A., Pastorczak, A., Mlynarski, W., Korshunov, A., Kumar, R., Downing, S., Pfister, S., Zapatka, M., McKinnon, P. J., Alt, F. W., Lichter, P., Ernst, A.. 2018-05-04. Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors. https://doi.org/10.1101/314518

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