Limits...
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.

Show MeSH

Related in: MedlinePlus

Generation of a Double Minute Chromosome Containing MYC by Chromothripsis in a Small Cell Lung Cancer Cell Line, SCLC-21H(A) Copy number profile, allelic ratio, and rearrangements of chromosome 8.(B) Copy number data from the rearrangement screen shows 15 discrete regions of chromosome 8 that are massively amplified, with 50–200 copies per cell. Each amplified region is demarcated by rearrangements linking to other heavily amplified segments (thick lines), with evidence for later internal rearrangements also found (thin lines).(C) Three color FISH for three regions of chromosome 8 (predicted to be linked by the rearrangement data, but not amplified; green, 13 Mb; red, 41 Mb; pale pink, 49 Mb).(D) FISH for three heavily amplified regions. The locations of the probes are shown in Figure 6B (red, 66.5 Mb; white, 99.3 Mb; green, 128.8 Mb).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3065307&req=5

fig6: Generation of a Double Minute Chromosome Containing MYC by Chromothripsis in a Small Cell Lung Cancer Cell Line, SCLC-21H(A) Copy number profile, allelic ratio, and rearrangements of chromosome 8.(B) Copy number data from the rearrangement screen shows 15 discrete regions of chromosome 8 that are massively amplified, with 50–200 copies per cell. Each amplified region is demarcated by rearrangements linking to other heavily amplified segments (thick lines), with evidence for later internal rearrangements also found (thin lines).(C) Three color FISH for three regions of chromosome 8 (predicted to be linked by the rearrangement data, but not amplified; green, 13 Mb; red, 41 Mb; pale pink, 49 Mb).(D) FISH for three heavily amplified regions. The locations of the probes are shown in Figure 6B (red, 66.5 Mb; white, 99.3 Mb; green, 128.8 Mb).

Mentions: One small cell lung cancer cell line, SCLC-21H, demonstrates massive numbers of copy number changes on chromosome 8, mostly with the typical appearances of chromothripsis (Figure S2A). Interestingly, however, the SNP array data suggest that some segments of the chromosome might be heavily amplified. We mapped 170 breakpoints, all involving chromosome 8 and showing the expected patterns of rearrangements described above (Figure 6A and Table S2). Whereas most of the chromosome oscillates among low copy number states, there are 15 discrete segments of the chromosome present at markedly increased copy number, ranging from 50 to 200 copies per cell (Figure 6B). One of these segments contains the MYC oncogene, amplified in 10%–20% of small cell lung cancers (Sher et al., 2008). The rearrangement data demonstrate that the 15 regions are interwoven by a series of rearrangements, many of which demarcate the starts and ends of the massively amplified segments. Strikingly, we found no evidence for breakpoints linking these massively amplified regions to the other, nonamplified but rearranged, regions of chromosome 8.


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)

Generation of a Double Minute Chromosome Containing MYC by Chromothripsis in a Small Cell Lung Cancer Cell Line, SCLC-21H(A) Copy number profile, allelic ratio, and rearrangements of chromosome 8.(B) Copy number data from the rearrangement screen shows 15 discrete regions of chromosome 8 that are massively amplified, with 50–200 copies per cell. Each amplified region is demarcated by rearrangements linking to other heavily amplified segments (thick lines), with evidence for later internal rearrangements also found (thin lines).(C) Three color FISH for three regions of chromosome 8 (predicted to be linked by the rearrangement data, but not amplified; green, 13 Mb; red, 41 Mb; pale pink, 49 Mb).(D) FISH for three heavily amplified regions. The locations of the probes are shown in Figure 6B (red, 66.5 Mb; white, 99.3 Mb; green, 128.8 Mb).
© Copyright Policy
Related In: Results  -  Collection

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

fig6: Generation of a Double Minute Chromosome Containing MYC by Chromothripsis in a Small Cell Lung Cancer Cell Line, SCLC-21H(A) Copy number profile, allelic ratio, and rearrangements of chromosome 8.(B) Copy number data from the rearrangement screen shows 15 discrete regions of chromosome 8 that are massively amplified, with 50–200 copies per cell. Each amplified region is demarcated by rearrangements linking to other heavily amplified segments (thick lines), with evidence for later internal rearrangements also found (thin lines).(C) Three color FISH for three regions of chromosome 8 (predicted to be linked by the rearrangement data, but not amplified; green, 13 Mb; red, 41 Mb; pale pink, 49 Mb).(D) FISH for three heavily amplified regions. The locations of the probes are shown in Figure 6B (red, 66.5 Mb; white, 99.3 Mb; green, 128.8 Mb).
Mentions: One small cell lung cancer cell line, SCLC-21H, demonstrates massive numbers of copy number changes on chromosome 8, mostly with the typical appearances of chromothripsis (Figure S2A). Interestingly, however, the SNP array data suggest that some segments of the chromosome might be heavily amplified. We mapped 170 breakpoints, all involving chromosome 8 and showing the expected patterns of rearrangements described above (Figure 6A and Table S2). Whereas most of the chromosome oscillates among low copy number states, there are 15 discrete segments of the chromosome present at markedly increased copy number, ranging from 50 to 200 copies per cell (Figure 6B). One of these segments contains the MYC oncogene, amplified in 10%–20% of small cell lung cancers (Sher et al., 2008). The rearrangement data demonstrate that the 15 regions are interwoven by a series of rearrangements, many of which demarcate the starts and ends of the massively amplified segments. Strikingly, we found no evidence for breakpoints linking these massively amplified regions to the other, nonamplified but rearranged, regions of chromosome 8.

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