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, the authors 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.
For the initial step, the authors determined that direct mechanical bridge breakage can generate simple breaks and local DNA fragmentation, providing one explanation for a rearrangement pattern frequently observed in cancer genomes termed “local jumps.” Concomitantly, there is defective DNA replication of bridge DNA, which the data suggest can generate complex rearrangements.
Some of these rearrangements exhibit a distinct sequence signature of tandem arrays of many short (~200 base pairs) insertions that we term “Tandem Short Template (TST) jumps.” The authors validated the presence of TST jumps in a human cancer by use of single-molecule long-read DNA sequencing.
Next, a second wave of DNA damage and increased chromothripsis occurs during the mitosis after bridge formation, when chromosomes from broken bridges undergo an unexpected burst of aberrant DNA replication. Last, these damaged bridge chromosomes missegregate with high frequency and form micronuclei in the following cell cycle, which can generate additional cycles of bridging, micronucleation, and chromothripsis.
Thus the authors 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.
Single cell division error may be responsible for complexity in cancer genomes
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