TY - JOUR
T1 - Constitutional Chromothripsis Rearrangements Involve Clustered Double-Stranded DNA Breaks and Nonhomologous Repair Mechanisms
AU - Kloosterman, Wigard P.
AU - Tavakoli-Yaraki, Masoumeh
AU - Van Roosmalen, Markus J.
AU - Van Binsbergen, Ellen
AU - Renkens, Ivo
AU - Duran, Karen
AU - Ballarati, Lucia
AU - Vergult, Sarah
AU - Giardino, Daniela
AU - Hansson, Kerstin
AU - Ruivenkamp, Claudia A.L.
AU - Jager, Myrthe
AU - Van Haeringen, Arie
AU - Ippel, Elly F.
AU - Haaf, Thomas
AU - Passarge, Eberhard
AU - Hochstenbach, Ron
AU - Menten, Björn
AU - Larizza, Lidia
AU - Guryev, Victor
AU - Poot, Martin
AU - Cuppen, Edwin
N1 - Funding Information:
We thank the patients and their parents for participation in this study. We thank Gijs van Haaften for critically reading the manuscript. The study was made possible by primary funding of the Department of Medical Genetics of the University Medical Center Utrecht to E.C.
PY - 2012/6/28
Y1 - 2012/6/28
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84863105790&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2012.05.009
DO - 10.1016/j.celrep.2012.05.009
M3 - Article
C2 - 22813740
AN - SCOPUS:84863105790
SN - 2211-1247
VL - 1
SP - 648
EP - 655
JO - Cell Reports
JF - Cell Reports
IS - 6
ER -