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 Guryev; Martin Poot; Edwin Cuppen

doi:10.1016/j.celrep.2012.05.009

Cell Reports (Jun 2012)

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 Guryev,
Martin Poot,
Edwin Cuppen

Affiliations

Wigard P. Kloosterman: Department of Medical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
Masoumeh Tavakoli-Yaraki: Department of Medical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
Markus J. van Roosmalen: Department of Medical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
Ellen van Binsbergen: Department of Medical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
Ivo Renkens: Department of Medical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
Karen Duran: Department of Medical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
Lucia Ballarati: Laboratorio di Citogenetica Medica e Genetica Molecolare, Centro di Ricerche e Tecnologie Biomediche, IRCCS-Istituto Auxologico Italiano, Via Ariosto 13, 20145 Milano, Italy
Sarah Vergult: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium
Daniela Giardino: Laboratorio di Citogenetica Medica e Genetica Molecolare, Centro di Ricerche e Tecnologie Biomediche, IRCCS-Istituto Auxologico Italiano, Via Ariosto 13, 20145 Milano, Italy
Kerstin Hansson: Leiden University Medical Center, Department of Clinical Genetics, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
Claudia A.L. Ruivenkamp: Leiden University Medical Center, Department of Clinical Genetics, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
Myrthe Jager: Department of Medical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
Arie van Haeringen: Leiden University Medical Center, Department of Clinical Genetics, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
Elly F. Ippel: Department of Medical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
Thomas Haaf: Institute of Human Genetics, Würzburg University, 97074 Würzburg, Germany
Eberhard Passarge: Institut für Humangenetik, Universitätsklinikum Essen, Hufelandstr. 55, D-45122 Essen, Germany
Ron Hochstenbach: Department of Medical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
Björn Menten: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium
Lidia Larizza: Laboratorio di Citogenetica Medica e Genetica Molecolare, Centro di Ricerche e Tecnologie Biomediche, IRCCS-Istituto Auxologico Italiano, Via Ariosto 13, 20145 Milano, Italy
Victor Guryev: Hubrecht Institute and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands
Martin Poot: Department of Medical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands
Edwin Cuppen: Department of Medical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands

DOI: https://doi.org/10.1016/j.celrep.2012.05.009
Journal volume & issue: Vol. 1, no. 6
pp. 648 – 655

Abstract

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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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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