Journal
SCIENCE
Volume 368, Issue 6488, Pages 282-+Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aba0712
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Funding
- Claudia Adams Barr Program for Innovative Cancer Research
- Cancer Research UK
- Royal College of Surgeons [C63474/A27176]
- National Cancer Institute (NCI) career transition award [K22CA216319]
- NCI Cancer Moonshot award [1R33CA225344]
- Harvard University Milton Fund
- NCI Mentored Clinical Scientist Research Career Development Award [K08CA208008]
- Burroughs-Wellcome Career Award for Medical Scientists (CAMS)
- NIH [GM083299]
- Research Investigator Award from the Lustgarten Foundation
- G. Harold and Leila Y. Mathers Charitable Foundation
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The chromosome breakage-fusion-bridge (BFB) cycle is a mutational process that produces gene amplification and genome instability. Signatures of BFB cycles can be observed in cancer genomes alongside chromothripsis, another catastrophic mutational phenomenon. We explain this association by elucidating a mutational cascade that is triggered by a single cell division error-chromosome bridge formation-that rapidly increases genomic complexity. We show that actomyosin forces are required for initial bridge breakage. Chromothripsis accumulates, beginning with aberrant interphase replication of bridge DNA. A subsequent burst of DNA replication in the next mitosis generates extensive DNA damage. During this second cell division, broken bridge chromosomes frequently missegregate and form micronuclei, promoting additional chromothripsis. We propose that iterations of this mutational cascade generate the continuing evolution and subclonal heterogeneity characteristic of many human cancers.
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