Massive genomic rearrangement acquired in a single catastrophic event during cancer development.
Bottom Line: Rearrangements involving one or a few chromosomes crisscross back and forth across involved regions, generating frequent oscillations between two copy number states.These genomic hallmarks are highly improbable if rearrangements accumulate over time and instead imply that nearly all occur during a single cellular catastrophe.We find that one, or indeed more than one, cancer-causing lesion can emerge out of the genomic crisis.
Affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.Show MeSH
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Mentions: A third feature arguing against the progressive rearrangement model is that breakpoints show significantly more clustering along the chromosome or chromosome arm than expected by chance (Figure 5D). A clean break across double-stranded DNA (dsDNA) generates two naked ends of which none, one or two may subsequently be repaired. Some of the clustering represents erroneous repair of both sides of a dsDNA break (see Figure 5B, for example). The extent of clustering observed in breakpoint locations, however, is much greater than explicable by this means alone. This presents some difficulties for the progressive rearrangements model because such nonrandom distribution of independently generated breaks would imply extensive regional variation in chromosomal fragility. Specific regions of increased propensity to rearrangement have been documented (Bignell et al., 2010), but not to the extent observed here. Under a catastrophe model, clustering among the prolific numbers of DNA breaks would perhaps be expected, depending on the process causing the DNA damage and repair. The limited overlap between sequences at the breakpoint junction suggests that the major mechanisms of DNA repair here are microhomology-mediated break repair and/or nonhomologous end-joining rather than homologous recombination (Figure S5).
Affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.