Chromosome segregation errors generate a diverse spectrum of simple and complex genomic rearrangements.

Autor: Ly P; Ludwig Institute for Cancer Research, Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA. peter.ly@utsouthwestern.edu.; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA. peter.ly@utsouthwestern.edu., Brunner SF; Wellcome Sanger Institute, Hinxton, UK., Shoshani O; Ludwig Institute for Cancer Research, Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA., Kim DH; Ludwig Institute for Cancer Research, Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA., Lan W; Ludwig Institute for Cancer Research, Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA., Pyntikova T; Whitehead Institute for Biomedical Research, Cambridge, MA, USA., Flanagan AM; University College London Cancer Institute, London, UK.; Department of Histopathology, Royal National Orthopaedic Hospital NHS Trust, Stanmore, UK., Behjati S; Wellcome Sanger Institute, Hinxton, UK.; Department of Paediatrics, University of Cambridge, Cambridge, UK., Page DC; Whitehead Institute for Biomedical Research, Cambridge, MA, USA.; Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, Cambridge, MA, USA.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA., Campbell PJ; Wellcome Sanger Institute, Hinxton, UK., Cleveland DW; Ludwig Institute for Cancer Research, Department of Cellular and Molecular Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA. dcleveland@ucsd.edu.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2019 Apr; Vol. 51 (4), pp. 705-715. Date of Electronic Publication: 2019 Mar 04.
DOI: 10.1038/s41588-019-0360-8
Abstrakt: Cancer genomes are frequently characterized by numerical and structural chromosomal abnormalities. Here we integrated a centromere-specific inactivation approach with selection for a conditionally essential gene, a strategy termed CEN-SELECT, to systematically interrogate the structural landscape of mis-segregated chromosomes. We show that single-chromosome mis-segregation into a micronucleus can directly trigger a broad spectrum of genomic rearrangement types. Cytogenetic profiling revealed that mis-segregated chromosomes exhibit 120-fold-higher susceptibility to developing seven major categories of structural aberrations, including translocations, insertions, deletions, and complex reassembly through chromothripsis coupled to classical non-homologous end joining. Whole-genome sequencing of clonally propagated rearrangements identified random patterns of clustered breakpoints with copy-number alterations resulting in interspersed gene deletions and extrachromosomal DNA amplification events. We conclude that individual chromosome segregation errors during mitotic cell division are sufficient to drive extensive structural variations that recapitulate genomic features commonly associated with human disease.
Databáze: MEDLINE
Externí odkaz: