Constitutional chromothripsis rearrangements involve clustered double-stranded DNA breaks and nonhomologous repair mechanisms.
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.
Department of Medical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands. w.kloosterman@umcutrecht.nl
Wigard P
WP
Kloosterman
Masoumeh
M
Tavakoli-Yaraki
Markus J
MJ
van Roosmalen
Ellen
E
van Binsbergen
Ivo
I
Renkens
Karen
K
Duran
Lucia
L
Ballarati
Sarah
S
Vergult
Daniela
D
Giardino
Kerstin
K
Hansson
Claudia A L
CA
Ruivenkamp
Myrthe
M
Jager
Arie
A
van Haeringen
Elly F
EF
Ippel
Thomas
T
Haaf
Eberhard
E
Passarge
Ron
R
Hochstenbach
Björn
B
Menten
Lidia
L
Larizza
Victor
V
Guryev
Martin
M
Poot
Edwin
E
Cuppen
D001483:Base Sequence; D019457:Chromosome Breakage; D002872:Chromosome Deletion; D058674:Chromosome Duplication / Q000235:genetics; D002877:Chromosomes, Human / Q000235:genetics*; D016000:Cluster Analysis; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics; D015321:Gene Rearrangement / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data