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Massive genomic rearrangement acquired in a single catastrophic event during cancer development.

Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, Pleasance ED, Lau KW, Beare D, Stebbings LA, McLaren S, Lin ML, McBride DJ, Varela I, Nik-Zainal S, Leroy C, Jia M, Menzies A, Butler AP, Teague JW, Quail MA, Burton J, Swerdlow H, Carter NP, Morsberger LA, Iacobuzio-Donahue C, Follows GA, Green AR, Flanagan AM, Stratton MR, Futreal PA, Campbell PJ - Cell (2011)

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.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

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Related in: MedlinePlus

Signatures of DNA Repair at the Breakpoint, Related to Figure 5Patterns of microhomology (red), non-templated sequence (teal) or direct end-joining (yellow) in the chromothripsis rearrangements for each sample. The x axis shows the number of bases of microhomology (right of 0) or non-templated sequence (left of 0) for each rearrangement. The y axis shows the number of rearrangements in the sample showing that pattern of microhomology or non-templated sequence.
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figs5: Signatures of DNA Repair at the Breakpoint, Related to Figure 5Patterns of microhomology (red), non-templated sequence (teal) or direct end-joining (yellow) in the chromothripsis rearrangements for each sample. The x axis shows the number of bases of microhomology (right of 0) or non-templated sequence (left of 0) for each rearrangement. The y axis shows the number of rearrangements in the sample showing that pattern of microhomology or non-templated sequence.

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).


Massive genomic rearrangement acquired in a single catastrophic event during cancer development.

Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ, Pleasance ED, Lau KW, Beare D, Stebbings LA, McLaren S, Lin ML, McBride DJ, Varela I, Nik-Zainal S, Leroy C, Jia M, Menzies A, Butler AP, Teague JW, Quail MA, Burton J, Swerdlow H, Carter NP, Morsberger LA, Iacobuzio-Donahue C, Follows GA, Green AR, Flanagan AM, Stratton MR, Futreal PA, Campbell PJ - Cell (2011)

Signatures of DNA Repair at the Breakpoint, Related to Figure 5Patterns of microhomology (red), non-templated sequence (teal) or direct end-joining (yellow) in the chromothripsis rearrangements for each sample. The x axis shows the number of bases of microhomology (right of 0) or non-templated sequence (left of 0) for each rearrangement. The y axis shows the number of rearrangements in the sample showing that pattern of microhomology or non-templated sequence.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3065307&req=5

figs5: Signatures of DNA Repair at the Breakpoint, Related to Figure 5Patterns of microhomology (red), non-templated sequence (teal) or direct end-joining (yellow) in the chromothripsis rearrangements for each sample. The x axis shows the number of bases of microhomology (right of 0) or non-templated sequence (left of 0) for each rearrangement. The y axis shows the number of rearrangements in the sample showing that pattern of microhomology or non-templated sequence.
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).

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.

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

Show MeSH
Related in: MedlinePlus