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

被引：166

作者：

Kloosterman, Wigard P. ^{[1
]}

Tavakoli-Yaraki, Masoumeh ^{[1
]}

van Roosmalen, Markus J. ^{[1
]}

van Binsbergen, Ellen ^{[1
]}

Renkens, Ivo ^{[1
]}

Duran, Karen ^{[1
]}

Ballarati, Lucia ^{[2
]}

Vergult, Sarah ^{[3
]}

Giardino, Daniela ^{[2
]}

Hansson, Kerstin ^{[4
]}

Ruivenkamp, Claudia A. L. ^{[4
]}

Jager, Myrthe ^{[1
]}

van Haeringen, Arie ^{[4
]}

Ippel, Elly F. ^{[1
]}

Haaf, Thomas ^{[5
]}

Passarge, Eberhard ^{[6
]}

Hochstenbach, Ron ^{[1
]}

Menten, Bjorn ^{[3
]}

Larizza, Lidia ^{[2
,7
]}

Guryev, Victor ^{[8
,9
]}

Poot, Martin ^{[1
]}

Cuppen, Edwin ^{[1
,8
,9
]}

机构：

[1] Univ Med Ctr Utrecht, Dept Med Genet, NL-3584 CG Utrecht, Netherlands

[2] IRCCS Ist Auxol Italiano, Ctr Ric & Tecnol Biomed, Lab Citogenet Med & Genet Mol, I-20145 Milan, Italy

[3] Ghent Univ Hosp, Ctr Med Genet, B-9000 Ghent, Belgium

[4] Leiden Univ, Med Ctr, Dept Clin Genet, NL-2333 AA Leiden, Netherlands

[5] Univ Wurzburg, Inst Human Genet, D-97074 Wurzburg, Germany

[6] Univ Klinikum Essen, Inst Humangenet, D-45122 Essen, Germany

[7] Univ Milan, San Paolo Sch Med, I-20142 Milan, Italy

[8] Univ Med Ctr Utrecht, NL-3584 CT Utrecht, Netherlands

[9] Hubrecht Inst, NL-3584 CT Utrecht, Netherlands

来源：

CELL REPORTS | 2012年 / 1卷 / 06期

关键词：

COMPLEX CHROMOSOMAL REARRANGEMENTS; DE-NOVO; BALANCED TRANSLOCATIONS; BREAKPOINTS; GENERATION; ORIGIN;

D O I：

10.1016/j.celrep.2012.05.009

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：648 / 655

页数：8

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