期刊
NATURE GENETICS
卷 51, 期 4, 页码 705-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41588-019-0360-8
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资金
- UCSD School of Medicine Microscopy Core [P30 NS047101]
- US National Institutes of Health [K99 CA218871, R35 GM122476]
- Wellcome Trust [WT088340MA, 110104/Z/15/Z]
- Hope Funds for Cancer Research [HFCR-14-06-06]
- Swiss National Science Foundation [P2SKP3171753, P400PB-180790]
- St. Baldricks Foundation (Robert J. Arceci Innovation Award)
- NIHR UCLH Biomedical Research Centre
- UCL Experimental Cancer Centre
- RNOH NHS Trust
- Howard Hughes Medical Institute
- Ludwig Institute for Cancer Research
- Swiss National Science Foundation (SNF) [P400PB_180790] Funding Source: Swiss National Science Foundation (SNF)
- Wellcome Trust [110104/Z/15/Z] Funding Source: Wellcome Trust
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.
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