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

Author

Listed:
  • Manasi Ratnaparkhe

    (Heidelberg University Germany)

  • John K. L. Wong

    (German Cancer Research Center (DKFZ))

  • Pei-Chi Wei

    (Harvard Medical School)

  • Mario Hlevnjak

    (German Cancer Research Center (DKFZ))

  • Thorsten Kolb

    (German Cancer Research Center (DKFZ))

  • Milena Simovic

    (Heidelberg University Germany)

  • Daniel Haag

    (Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ))

  • Yashna Paul

    (German Cancer Research Center (DKFZ))

  • Frauke Devens

    (German Cancer Research Center (DKFZ))

  • Paul Northcott

    (German Cancer Research Center (DKFZ)
    St. Jude Children’s Research Hospital)

  • David T. W. Jones

    (Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ))

  • Marcel Kool

    (Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ))

  • Anna Jauch

    (University of Heidelberg)

  • Agata Pastorczak

    (Medical University of Lodz)

  • Wojciech Mlynarski

    (Medical University of Lodz)

  • Andrey Korshunov

    (Heidelberg University Hospital and German Cancer Consortium (DKTK))

  • Rajiv Kumar

    (German Cancer Research Center)

  • Susanna M. Downing

    (St. Jude Children’s Research Hospital)

  • Stefan M. Pfister

    (Hopp Children’s Cancer Center at the NCT Heidelberg (KiTZ))

  • Marc Zapatka

    (German Cancer Research Center (DKFZ))

  • Peter J. McKinnon

    (St. Jude Children’s Research Hospital)

  • Frederick W. Alt

    (Harvard Medical School)

  • Peter Lichter

    (German Cancer Research Center (DKFZ))

  • Aurélie Ernst

    (German Cancer Research Center (DKFZ))

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.

Suggested Citation

  • 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 & An, 2018. "Defective DNA damage repair leads to frequent catastrophic genomic events in murine and human tumors," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06925-4
    DOI: 10.1038/s41467-018-06925-4
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    Cited by:

    1. Xue-Ke Zhao & Pengwei Xing & Xin Song & Miao Zhao & Linxuan Zhao & Yonglong Dang & Ling-Ling Lei & Rui-Hua Xu & Wen-Li Han & Pan-Pan Wang & Miao-Miao Yang & Jing-Feng Hu & Kan Zhong & Fu-You Zhou & Xu, 2021. "Focal amplifications are associated with chromothripsis events and diverse prognoses in gastric cardia adenocarcinoma," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    2. Junho Kim & August Yue Huang & Shelby L. Johnson & Jenny Lai & Laura Isacco & Ailsa M. Jeffries & Michael B. Miller & Michael A. Lodato & Christopher A. Walsh & Eunjung Alice Lee, 2022. "Prevalence and mechanisms of somatic deletions in single human neurons during normal aging and in DNA repair disorders," Nature Communications, Nature, vol. 13(1), pages 1-13, December.

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