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Single Error in Cell Division Can Generate Great Complexity in Cancer Genomes

NEW YORK – A single error in cell division may lead to a chain of mutations that generate the complexity seen in many cancer genomes, according to a new study.

Cancer genomes can contain hundreds of chromosomal rearrangements. The conventional view is that they accrue small-scale changes over many generations, but the large number of rearrangements in many cancers suggests that these genomes may actually evolve rapidly through discrete episodes that generate bursts of genomic alterations, the researchers wrote in a paper published on Thursday in Science.

There are four classes of catastrophic events that may account for a substantial fraction of chromosome alterations in cancer: whole-genome duplication, chromoplexy, chromothripsis, and chromosome breakage-fusion-bridge (BFB) cycles. Whole-genome duplication can promote tumorigenesis, and chromoplexy is a balanced chains of rearrangements between multiple chromosomes.

The third class, chromothripsis, is the extensive rearrangement of only one or a few chromosomes, generating a characteristic DNA copy number pattern. It occurs with frequencies of 20 percent to 65 percent in certain common tumor types, the researchers noted. The chromosome BFB cycle, meanwhile, starts with the formation of another abnormal nuclear structure, a chromosome bridge. These bridges arise from end-to-end chromosome fusions after DNA breakage or telomere crisis, incomplete DNA replication, or failed resolution of chromosome catenation. Bridge breakage then initiates a process that can generate gene amplification over multiple cell generations. Although BFB cycles are a major source of genome instability, they're commonly observed in cancer genomes without other chromosome alterations.

Recently, however, cancer genomes were identified in which BFB cycles were intermingled with chromothripsis, raising the possibility that BFB cycles and chromothripsis might be mechanistically related. In their study, the researchers explained 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. Chromothripsis accumulates, beginning with aberrant interphase replication of bridge DNA," they wrote. "A subsequent burst of DNA replication in the next mitosis generates extensive DNA damage. During this second cell division, broken bridge chromosomes frequently missegregate and form micronuclei, promoting additional chromothripsis. We propose that iterations of this mutational cascade generate the continuing evolution and subclonal heterogeneity characteristic of many human cancers."

The researchers noted that their results identified 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. This shows that episodes of chromothripsis are interwoven with multiple steps of the BFB cycle and could necessitate a revision of the chromosome BFB model.

They proposed a model in which the assembly of the nuclear envelope around the chromosome bridge is aberrant, leading to depletion of nuclear pores, which leads to a defective nucleoplasm when combined with bridge geometry. This results in poor DNA replication in the bridge, producing stalled replication forks and replication origins that have not fired. The bridge is then broken by a mechanism that requires a stretching force from the actin cytoskeleton.

Bridge breakage produces simple breaks and local fragmentation, generating free DNA ends that can engage in end-joining or error-prone replicative repair. These events lead to a low frequency of chromothripsis during the interphase, in which the bridge forms and breaks. Subsequently, the stubs of broken chromosome bridges undergo a burst of aberrant mitotic DNA replication, which leads to significantly more DNA damage and increases the frequency of chromothripsis. Finally, bridge formation compromises centromere function, which increases the rate of micronucleation during the next cell division after bridge formation. These micronuclei generate further cycles of chromothripsis, and all of these combined mutational events rapidly generate hallmark features of cancer genome complexity.

"Together, our findings identify mechanisms that explain the remarkable potential of a single unrepaired DNA break to compromise the integrity of the genome," the authors concluded.