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Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis.

Nones K, Waddell N, Wayte N, Patch AM, Bailey P, Newell F, Holmes O, Fink JL, Quinn MC, Tang YH, Lampe G, Quek K, Loffler KA, Manning S, Idrisoglu S, Miller D, Xu Q, Waddell N, Wilson PJ, Bruxner TJ, Christ AN, Harliwong I, Nourse C, Nourbakhsh E, Anderson M, Kazakoff S, Leonard C, Wood S, Simpson PT, Reid LE, Krause L, Hussey DJ, Watson DI, Lord RV, Nancarrow D, Phillips WA, Gotley D, Smithers BM, Whiteman DC, Hayward NK, Campbell PJ, Pearson JV, Grimmond SM, Barbour AP - Nat Commun (2014)

Bottom Line: While large EAC exome sequencing efforts to date have found recurrent loss-of-function mutations, oncogenic driving events have been underrepresented.Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations.These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC.

View Article: PubMed Central - PubMed

Affiliation: 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia [2] QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.

ABSTRACT
Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-of-function mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n=40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC.

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Chromothripsis and breakage-fusion-bridge (BFB) evidence in an EAC tumourOESO_3845 contained a high number of SVs concentrated in two chromosomes, 12 and 18. (a) Circos plot shows overall distribution of SVs in the genome. Circos plot containing copy number and B-allele frequency in the outer rings and somatic structural variants (SVs) are represented by lines in the inner ring. Colour of the lines represents SV type as indicated in the legend. (b) Zoomed-in view of events on chromosome 12. Graph shows from the top, SVs, copy number, logR ratio and B-allele frequency. Copy number profile suggests loss of telomeric p arm and SV events suggest several cycles of BFB on chromosome 12, with 20 inversions mapped to the amplified region (24,387,412 to 28,333,288 bp). (c) Zoomed-in view of events on chromosome 18. Graph shows SVs, copy number, logR ratio and B-allele frequency. SV events and copy number data suggests shattering of chromosome 18 with switches in copy number state, concentration of a high number of SVs and retention of heterozygosity characteristic of a chromothriptic event.
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Figure 4: Chromothripsis and breakage-fusion-bridge (BFB) evidence in an EAC tumourOESO_3845 contained a high number of SVs concentrated in two chromosomes, 12 and 18. (a) Circos plot shows overall distribution of SVs in the genome. Circos plot containing copy number and B-allele frequency in the outer rings and somatic structural variants (SVs) are represented by lines in the inner ring. Colour of the lines represents SV type as indicated in the legend. (b) Zoomed-in view of events on chromosome 12. Graph shows from the top, SVs, copy number, logR ratio and B-allele frequency. Copy number profile suggests loss of telomeric p arm and SV events suggest several cycles of BFB on chromosome 12, with 20 inversions mapped to the amplified region (24,387,412 to 28,333,288 bp). (c) Zoomed-in view of events on chromosome 18. Graph shows SVs, copy number, logR ratio and B-allele frequency. SV events and copy number data suggests shattering of chromosome 18 with switches in copy number state, concentration of a high number of SVs and retention of heterozygosity characteristic of a chromothriptic event.

Mentions: Chromothripsis has been reported in different cancer types25–28 and was initially thought to be present in 2 to 3% of tumours25. Zack et al.29 detected chromothripsis in 5% of tumours across 10 cancer types, ranging from 0 to 16%, however, higher frequency has been reported in bone cancer (25%)25 and medulloblastoma (36%)27. The prevalence of chromothripsis in cancer genomes has been recently reviewed by Kloosterman et al.30 This catastrophic event is a plausible explanation for the concentration of SVs in one or few chromosomes observed in EACs with complex localized genomes. Mitotic chromosome segregation errors that lead to chromosome shattering (chromothripsis)25,31 can affect several genes in only a few cell cycles and have the potential to drive cancer development25. Such events may represent an alternative mechanism to the stepwise accumulation of mutations that lead to malignant transformation. Surprisingly, eight of the 22 EACs (36%) in the discovery cohort contained rearrangements similar to chromothripsis (Figs 2–4, Supplementary Figs 5 and 6, Supplementary Data 10 and 11). This high frequency of chromothripsis was confirmed by screening a further 101 EACs using SNP arrays, with 32 out of 101 (32%) tumours showing ≥10 transitions between 2 or 3 copy number states, with loss and preservation of heterozygosity in one or few chromosomes (Supplementary Fig. 7). In total, 40 EACs out of 123 tumours (32.5%) showed evidence of chromothripsis.


Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis.

Nones K, Waddell N, Wayte N, Patch AM, Bailey P, Newell F, Holmes O, Fink JL, Quinn MC, Tang YH, Lampe G, Quek K, Loffler KA, Manning S, Idrisoglu S, Miller D, Xu Q, Waddell N, Wilson PJ, Bruxner TJ, Christ AN, Harliwong I, Nourse C, Nourbakhsh E, Anderson M, Kazakoff S, Leonard C, Wood S, Simpson PT, Reid LE, Krause L, Hussey DJ, Watson DI, Lord RV, Nancarrow D, Phillips WA, Gotley D, Smithers BM, Whiteman DC, Hayward NK, Campbell PJ, Pearson JV, Grimmond SM, Barbour AP - Nat Commun (2014)

Chromothripsis and breakage-fusion-bridge (BFB) evidence in an EAC tumourOESO_3845 contained a high number of SVs concentrated in two chromosomes, 12 and 18. (a) Circos plot shows overall distribution of SVs in the genome. Circos plot containing copy number and B-allele frequency in the outer rings and somatic structural variants (SVs) are represented by lines in the inner ring. Colour of the lines represents SV type as indicated in the legend. (b) Zoomed-in view of events on chromosome 12. Graph shows from the top, SVs, copy number, logR ratio and B-allele frequency. Copy number profile suggests loss of telomeric p arm and SV events suggest several cycles of BFB on chromosome 12, with 20 inversions mapped to the amplified region (24,387,412 to 28,333,288 bp). (c) Zoomed-in view of events on chromosome 18. Graph shows SVs, copy number, logR ratio and B-allele frequency. SV events and copy number data suggests shattering of chromosome 18 with switches in copy number state, concentration of a high number of SVs and retention of heterozygosity characteristic of a chromothriptic event.
© Copyright Policy - permissions-link - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4596003&req=5

Figure 4: Chromothripsis and breakage-fusion-bridge (BFB) evidence in an EAC tumourOESO_3845 contained a high number of SVs concentrated in two chromosomes, 12 and 18. (a) Circos plot shows overall distribution of SVs in the genome. Circos plot containing copy number and B-allele frequency in the outer rings and somatic structural variants (SVs) are represented by lines in the inner ring. Colour of the lines represents SV type as indicated in the legend. (b) Zoomed-in view of events on chromosome 12. Graph shows from the top, SVs, copy number, logR ratio and B-allele frequency. Copy number profile suggests loss of telomeric p arm and SV events suggest several cycles of BFB on chromosome 12, with 20 inversions mapped to the amplified region (24,387,412 to 28,333,288 bp). (c) Zoomed-in view of events on chromosome 18. Graph shows SVs, copy number, logR ratio and B-allele frequency. SV events and copy number data suggests shattering of chromosome 18 with switches in copy number state, concentration of a high number of SVs and retention of heterozygosity characteristic of a chromothriptic event.
Mentions: Chromothripsis has been reported in different cancer types25–28 and was initially thought to be present in 2 to 3% of tumours25. Zack et al.29 detected chromothripsis in 5% of tumours across 10 cancer types, ranging from 0 to 16%, however, higher frequency has been reported in bone cancer (25%)25 and medulloblastoma (36%)27. The prevalence of chromothripsis in cancer genomes has been recently reviewed by Kloosterman et al.30 This catastrophic event is a plausible explanation for the concentration of SVs in one or few chromosomes observed in EACs with complex localized genomes. Mitotic chromosome segregation errors that lead to chromosome shattering (chromothripsis)25,31 can affect several genes in only a few cell cycles and have the potential to drive cancer development25. Such events may represent an alternative mechanism to the stepwise accumulation of mutations that lead to malignant transformation. Surprisingly, eight of the 22 EACs (36%) in the discovery cohort contained rearrangements similar to chromothripsis (Figs 2–4, Supplementary Figs 5 and 6, Supplementary Data 10 and 11). This high frequency of chromothripsis was confirmed by screening a further 101 EACs using SNP arrays, with 32 out of 101 (32%) tumours showing ≥10 transitions between 2 or 3 copy number states, with loss and preservation of heterozygosity in one or few chromosomes (Supplementary Fig. 7). In total, 40 EACs out of 123 tumours (32.5%) showed evidence of chromothripsis.

Bottom Line: While large EAC exome sequencing efforts to date have found recurrent loss-of-function mutations, oncogenic driving events have been underrepresented.Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations.These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC.

View Article: PubMed Central - PubMed

Affiliation: 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia [2] QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.

ABSTRACT
Oesophageal adenocarcinoma (EAC) incidence is rapidly increasing in Western countries. A better understanding of EAC underpins efforts to improve early detection and treatment outcomes. While large EAC exome sequencing efforts to date have found recurrent loss-of-function mutations, oncogenic driving events have been underrepresented. Here we use a combination of whole-genome sequencing (WGS) and single-nucleotide polymorphism-array profiling to show that genomic catastrophes are frequent in EAC, with almost a third (32%, n=40/123) undergoing chromothriptic events. WGS of 22 EAC cases show that catastrophes may lead to oncogene amplification through chromothripsis-derived double-minute chromosome formation (MYC and MDM2) or breakage-fusion-bridge (KRAS, MDM2 and RFC3). Telomere shortening is more prominent in EACs bearing localized complex rearrangements. Mutational signature analysis also confirms that extreme genomic instability in EAC can be driven by somatic BRCA2 mutations. These findings suggest that genomic catastrophes have a significant role in the malignant transformation of EAC.

Show MeSH
Related in: MedlinePlus