Somatic copy number and structural variation in RPE-1 cells with induced chromosomal instability
Authors/Creators
- 1. Dana-Farber Cancer Institute
- 2. Wellcome Sanger Institute
Description
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. Here, we explain this association by elucidating a mutational cascade, downstream of the single cell division error of chromosome bridge formation, that rapidly generates extreme genomic complexity. We show that actomyosin forces are required for initial bridge breakage and mutagenesis, following which chromothripsis accumulates with aberrant interphase replication of bridge DNA. This is then followed by an unexpected burst of DNA replication in the next mitosis, generating extensive DNA damage. During this second cell division, broken bridge chromosomes frequently mis-segregate and form micronuclei, promoting additional chromothripsis. We further show that this mutational cascade generates the continuing evolution and sub-clonal heterogeneity characteristic of many human cancers.
Notes
Raw WGS sequencing data for these samples are available via the Sequence Read Archive (SRA) under BioProject PRJNA602546.
Funding provided by: National Institutes of Health
Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000002
Award Number: GM083299
Funding provided by: National Institutes of Health
Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000002
Award Number: K08CA208008
Funding provided by: National Cancer Institute
Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000054
Award Number: 1R33CA225344
Funding provided by: Cancer Research UK
Crossref Funder Registry ID: http://dx.doi.org/10.13039/501100000289
Award Number: C63474/A27176
Funding provided by: National Cancer Institute
Crossref Funder Registry ID: http://dx.doi.org/10.13039/100000054
Award Number: K22CA216319
Files
1a_CNV_all.pdf
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