TY - JOUR
T1 - Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements
AU - Liu, Pengfei
AU - Erez, Ayelet
AU - Nagamani, Sandesh C Sreenath
AU - Dhar, Shweta U.
AU - Kołodziejska, Katarzyna E.
AU - Dharmadhikari, Avinash V.
AU - Cooper, M. Lance
AU - Wiszniewska, Joanna
AU - Zhang, Feng
AU - Withers, Marjorie A.
AU - Bacino, Carlos A.
AU - Campos-Acevedo, Luis Daniel
AU - Delgado, Mauricio R.
AU - Freedenberg, Debra
AU - Garnica, Adolfo
AU - Grebe, Theresa A.
AU - Hernández-Almaguer, Dolores
AU - Immken, Ladonna
AU - Lalani, Seema R.
AU - McLean, Scott D.
AU - Northrup, Hope
AU - Scaglia, Fernando
AU - Strathearn, Lane
AU - Trapane, Pamela
AU - Kang, Sung Hae L
AU - Patel, Ankita
AU - Cheung, Sau Wai
AU - Hastings, P. J.
AU - Stankiewicz, Paweł
AU - Lupski, James R.
AU - Bi, Weimin
N1 - Funding Information:
We thank the patients and their families for participation in this research, the Molecular Cytogenetics Laboratories in the MGL at BCM ( https://www.bcm.edu/geneticlabs/ ) for providing technical support, Dr. Katarzyna Derwinska for helpful discussion, and Roche NimbleGen for supplying NimbleGen aCGH materials. This work was supported in part by National Institute of Neurological Disorders and Stroke, National Institutes of Health grant R01 NS058529 to J.R.L., National Institutes of General Medical Science grant R01 GM064022 to P.J.H., and the BCM IDDRC P30HD024064 funded from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. A.E. is supported by DK081735-02 and S.C.S.N. is supported by a fellowship grants by the LCRC from the Osteogenesis Imperfecta Foundation and the National Urea Cycle Disorders Foundation. J.R.L. is a consultant for Athena Diagnostics, has stock ownership in 23andMe and Ion Torrent Systems and is a coinventor on multiple United States and European patents for DNA diagnostics. The Department of Molecular and Human Genetics derives revenue from clinical testing by high-resolution human genome analysis.
PY - 2011/9/16
Y1 - 2011/9/16
N2 - Complex genomic rearrangements (CGRs) consisting of two or more breakpoint junctions have been observed in genomic disorders. Recently, a chromosome catastrophe phenomenon termed chromothripsis, in which numerous genomic rearrangements are apparently acquired in one single catastrophic event, was described in multiple cancers. Here, we show that constitutionally acquired CGRs share similarities with cancer chromothripsis. In the 17 CGR cases investigated, we observed localization and multiple copy number changes including deletions, duplications, and/or triplications, as well as extensive translocations and inversions. Genomic rearrangements involved varied in size and complexities; in one case, array comparative genomic hybridization revealed 18 copy number changes. Breakpoint sequencing identified characteristic features, including small templated insertions at breakpoints and microhomology at breakpoint junctions, which have been attributed to replicative processes. The resemblance between CGR and chromothripsis suggests similar mechanistic underpinnings. Such chromosome catastrophic events appear to reflect basic DNA metabolism operative throughout an organism's life cycle.
AB - Complex genomic rearrangements (CGRs) consisting of two or more breakpoint junctions have been observed in genomic disorders. Recently, a chromosome catastrophe phenomenon termed chromothripsis, in which numerous genomic rearrangements are apparently acquired in one single catastrophic event, was described in multiple cancers. Here, we show that constitutionally acquired CGRs share similarities with cancer chromothripsis. In the 17 CGR cases investigated, we observed localization and multiple copy number changes including deletions, duplications, and/or triplications, as well as extensive translocations and inversions. Genomic rearrangements involved varied in size and complexities; in one case, array comparative genomic hybridization revealed 18 copy number changes. Breakpoint sequencing identified characteristic features, including small templated insertions at breakpoints and microhomology at breakpoint junctions, which have been attributed to replicative processes. The resemblance between CGR and chromothripsis suggests similar mechanistic underpinnings. Such chromosome catastrophic events appear to reflect basic DNA metabolism operative throughout an organism's life cycle.
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U2 - 10.1016/j.cell.2011.07.042
DO - 10.1016/j.cell.2011.07.042
M3 - Article
C2 - 21925314
AN - SCOPUS:80052916562
SN - 0092-8674
VL - 146
SP - 889
EP - 903
JO - Cell
JF - Cell
IS - 6
ER -