Constitutional Chromothripsis Rearrangements Involve Clustered Double-Stranded DNA Breaks and Nonhomologous Repair Mechanisms

Wigard P. Kloosterman, Masoumeh Tavakoli-Yaraki, Markus J. Van Roosmalen, Ellen Van Binsbergen, Ivo Renkens, Karen Duran, Lucia Ballarati, Sarah Vergult, Daniela Giardino, Kerstin Hansson, Claudia A L Ruivenkamp, Myrthe Jager, Arie Van Haeringen, Elly F. Ippel, Thomas Haaf, Eberhard Passarge, Ron Hochstenbach, Björn Menten, Lidia Larizza, Victor GuryevMartin Poot, Edwin Cuppen

Research output: Contribution to journalArticlepeer-review


Chromothripsis represents a novel phenomenon in the structural variation landscape of cancer genomes. Here, we analyze the genomes of ten patients with congenital disease who were preselected to carry complex chromosomal rearrangements with more than two breakpoints. The rearrangements displayed unanticipated complexity resembling chromothripsis. We find that eight of them contain hallmarks of multiple clustered double-stranded DNA breaks (DSBs) on one or more chromosomes. In addition, nucleotide resolution analysis of 98 breakpoint junctions indicates that break repair involves nonhomologous or microhomology-mediated end joining. We observed that these eight rearrangements are balanced or contain sporadic deletions ranging in size between a few hundred base pairs and several megabases. The two remaining complex rearrangements did not display signs of DSBs and contain duplications, indicative of rearrangement processes involving template switching. Our work provides detailed insight into the characteristics of chromothripsis and supports a role for clustered DSBs driving some constitutional chromothripsis rearrangements.

Original languageEnglish
Pages (from-to)648-655
Number of pages8
JournalCell Reports
Issue number6
Publication statusPublished - Jun 28 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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