Somatic copy number and structural variation in RPE-1 cells with induced chromosomal instability

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.