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

<p><span><span><span><span><span><span><span><span><span><span><span>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 <a>th</a></span></span></span></span></span></span></span></span></span></span></span><span><span><span><span><span><span><span><span><span><span><span>e 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 <a>fu</a></span></span></span></span></span></span></span></span></span></span></span><span><span><span><span><span><span><span><span><span><span><span>rther show that this mutational cascade generates the continuing evolution and sub-clonal heterogeneity characteristic of many human cancers.</span></span></span></span></span></span></span></span></span></span></span></p>