Abstract
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.
Highlights
Cancer genomes can contain hundreds of chromosomal rearrangements [1]
Chromosome bridges were visualized in live cells with GFP-BAF [barrier-to-autointegration factor [33]], a sensitive reporter for these structures whose signal is not compromised by stretching of the bridge (Fig. 1), unlike fluorescent histone reporters [28]
Our results identify a cascade of events that generate increasing amounts of chromothripsis after the formation of a chromosome bridge, creating many hallmark features of cancer genomes from a single cell division error
Summary
Cancer genomes can contain hundreds of chromosomal rearrangements [1]. Traditionally, it was assumed that these genomes evolve gradually by accruing small-scale changes successively over many generations. The high number of rearrangements in many cancers suggests a non-exclusive, alternative view: cancer genomes may evolve rapidly via discrete episodes that generate bursts of genomic alterations [1,2,3,4,5,6,7,8]. This model is appealing because a small number of catastrophic mutational events can parsimoniously explain the origin of extreme complexity in many cancer genomes [4]. The first class, whole-genome duplication, can promote tumorigenesis [3] and is appreciated to occur during the development of ~40% of human solid tumors [9]
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