A single error in cell division related to the formation of a chromosome bridge can trigger a cascade of mutational events, rapidly generating many of the defining features of cancer genomes, a new study suggests. The findings provide a potential mechanistic explanation for the extreme genomic complexity and chromosomal rearrangements found in certain tumor types. It's been assumed that cancer genomes acquire their complexity gradually, accumulating small-scale changes over time through unavoidable errors during DNA replication. However, some studies have suggested that cancer genomes may also evolve rapidly through one-off catastrophic mutational events that generate bursts of genomic alterations. Researchers know the scrambled genomes of cancer cells can arise quickly via several mutational processes, including the chromosome breakage-fusion-bridge (BFB) cycle and chromothripsis - a highly local, yet massive rearrangement in one or several chromosomes. Recent studies have suggested that these two catastrophic mutational processes may be mechanistically related. To evaluate their relationship, Neil Umbreit and colleagues recreated the essential steps of the BFB cycle in cultured cells and used live cell imaging and single-cell whole-genome sequencing to observe the downstream genetic repercussions of aberrant cell division, specifically of aberrant chromosome bridge formation. Umbreit et al. discovered that this single error during one cell division triggered a mutational avalanche that generated increasing amounts of chromothripsis, resulting in rapid and extensive DNA damage. In a related Perspective, Jacob Paiano and André Nussenzweig discuss the study in greater detail.
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Science