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; Aurélie Ernst

doi:10.1038/s41467-018-06925-4

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, Aurélie Ernst

Research output: Contribution to journal › Article › peer-review

71 Citations (Scopus)

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.

Original language	English
Article number	4760
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-06925-4
Publication status	Published - 1 Dec 2018
Externally published	Yes

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Ratnaparkhe, M., Wong, J. K. L., Wei, P. C., Hlevnjak, M., Kolb, T., Simovic, M., Haag, D., Paul, Y., Devens, F., Northcott, P., Jones, D. T. W., Kool, M., Jauch, A., Pastorczak, A., Mlynarski, W., Korshunov, A., Kumar, R., Downing, S. M., Pfister, S. M., ... Ernst, A. (2018). Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors. Nature communications, 9(1), Article 4760. https://doi.org/10.1038/s41467-018-06925-4

@article{374910eb47d74534ae903fc7fa848625,

title = "Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors",

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.",

author = "Manasi Ratnaparkhe and Wong, \{John K.L.\} and Wei, \{Pei Chi\} and Mario Hlevnjak and Thorsten Kolb and Milena Simovic and Daniel Haag and Yashna Paul and Frauke Devens and Paul Northcott and Jones, \{David T.W.\} and Marcel Kool and Anna Jauch and Agata Pastorczak and Wojciech Mlynarski and Andrey Korshunov and Rajiv Kumar and Downing, \{Susanna M.\} and Pfister, \{Stefan M.\} and Marc Zapatka and McKinnon, \{Peter J.\} and Alt, \{Frederick W.\} and Peter Lichter and Aur{\'e}lie Ernst",

note = "Publisher Copyright: {\textcopyright} 2018, The Author(s).",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-06925-4",

language = "English",

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Ratnaparkhe, M, Wong, JKL, Wei, PC, Hlevnjak, M, Kolb, T, Simovic, M, Haag, D, Paul, Y, Devens, F, Northcott, P, Jones, DTW, Kool, M, Jauch, A, Pastorczak, A, Mlynarski, W, Korshunov, A, Kumar, R, Downing, SM, Pfister, SM, Zapatka, M, McKinnon, PJ, Alt, FW, Lichter, P & Ernst, A 2018, 'Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors', Nature communications, vol. 9, no. 1, 4760. https://doi.org/10.1038/s41467-018-06925-4

TY - JOUR

T1 - Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors

AU - Ratnaparkhe, Manasi

AU - Wong, John K.L.

AU - Wei, Pei Chi

AU - Hlevnjak, Mario

AU - Kolb, Thorsten

AU - Simovic, Milena

AU - Haag, Daniel

AU - Paul, Yashna

AU - Devens, Frauke

AU - Northcott, Paul

AU - Jones, David T.W.

AU - Kool, Marcel

AU - Jauch, Anna

AU - Pastorczak, Agata

AU - Mlynarski, Wojciech

AU - Korshunov, Andrey

AU - Kumar, Rajiv

AU - Downing, Susanna M.

AU - Pfister, Stefan M.

AU - Zapatka, Marc

AU - McKinnon, Peter J.

AU - Alt, Frederick W.

AU - Lichter, Peter

AU - Ernst, Aurélie

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85056307498

U2 - 10.1038/s41467-018-06925-4

DO - 10.1038/s41467-018-06925-4

M3 - Article

C2 - 30420702

AN - SCOPUS:85056307498

SN - 2041-1723

VL - 9

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 4760

ER -

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

Abstract

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