MECHANISMS GENERATING CANCER GENOME COMPLEXITY FROM A SINGLE CELL DIVISION ERROR

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 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, following which chromothripsis accumulates beginning 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 iterations of this mutational cascade generate the continuing evolution and sub-clonal heterogeneity characteristic of many human cancers.