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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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Evidence of chromothripsis in EAC tumours(a) Circos plot of tumour OESO_1527 containing copy number and BAF 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. Circos plot37 shows a high concentration of SVs on chromosome 9. (b) Zoomed-in view of events on chromosome 9 of tumour OESO_1527 showing evidence of chromosome shattering (chromothripsis). From top to bottom, graphs show SVs, copy number, logR ratio and BAF. There are changes in copy number state, concentration of a high number of SVs and retention of heterozygosity. (c) The genome distribution of somatic SVs for tumour OESO_3213. Circos plot containing copy number and SVs shows a concentration of events on chromosome 8. (d) Zoomed-in view of events on chromosome 8 in OESO_3213 showing SVs, copy number, logR ratio and B-allele frequency. (e) Inferred double-minute chromosome (DM) harbouring MYC oncogene. Blue blocks show fragments of chromosome 8 inferred to form DM and green block shows position of FISH probe. (f) Agarose gel showing PCR verification of SV events inferred to contribute to the DM. T, tumour, N, adjacent normal esophagus, numbers indicate SVs as shown in e. (g) FISH confirms copy number alterations in d by showing MYC amplification as multiple scattered signals and two copies of the chromosome 8 in a representative tumour cell nucleus. (Green—fluorescently labelled BAC RP11-367L7—MYC gene region; Red—centromeric region of chromosome 8—CHR8-10-RE). Scale bar, 10 μm. Supplementary Figures 11 and 12 are full images of gel and FISH presented in (f) and (g), respectively.
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Figure 2: Evidence of chromothripsis in EAC tumours(a) Circos plot of tumour OESO_1527 containing copy number and BAF 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. Circos plot37 shows a high concentration of SVs on chromosome 9. (b) Zoomed-in view of events on chromosome 9 of tumour OESO_1527 showing evidence of chromosome shattering (chromothripsis). From top to bottom, graphs show SVs, copy number, logR ratio and BAF. There are changes in copy number state, concentration of a high number of SVs and retention of heterozygosity. (c) The genome distribution of somatic SVs for tumour OESO_3213. Circos plot containing copy number and SVs shows a concentration of events on chromosome 8. (d) Zoomed-in view of events on chromosome 8 in OESO_3213 showing SVs, copy number, logR ratio and B-allele frequency. (e) Inferred double-minute chromosome (DM) harbouring MYC oncogene. Blue blocks show fragments of chromosome 8 inferred to form DM and green block shows position of FISH probe. (f) Agarose gel showing PCR verification of SV events inferred to contribute to the DM. T, tumour, N, adjacent normal esophagus, numbers indicate SVs as shown in e. (g) FISH confirms copy number alterations in d by showing MYC amplification as multiple scattered signals and two copies of the chromosome 8 in a representative tumour cell nucleus. (Green—fluorescently labelled BAC RP11-367L7—MYC gene region; Red—centromeric region of chromosome 8—CHR8-10-RE). Scale bar, 10 μm. Supplementary Figures 11 and 12 are full images of gel and FISH presented in (f) and (g), respectively.

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)

Evidence of chromothripsis in EAC tumours(a) Circos plot of tumour OESO_1527 containing copy number and BAF 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. Circos plot37 shows a high concentration of SVs on chromosome 9. (b) Zoomed-in view of events on chromosome 9 of tumour OESO_1527 showing evidence of chromosome shattering (chromothripsis). From top to bottom, graphs show SVs, copy number, logR ratio and BAF. There are changes in copy number state, concentration of a high number of SVs and retention of heterozygosity. (c) The genome distribution of somatic SVs for tumour OESO_3213. Circos plot containing copy number and SVs shows a concentration of events on chromosome 8. (d) Zoomed-in view of events on chromosome 8 in OESO_3213 showing SVs, copy number, logR ratio and B-allele frequency. (e) Inferred double-minute chromosome (DM) harbouring MYC oncogene. Blue blocks show fragments of chromosome 8 inferred to form DM and green block shows position of FISH probe. (f) Agarose gel showing PCR verification of SV events inferred to contribute to the DM. T, tumour, N, adjacent normal esophagus, numbers indicate SVs as shown in e. (g) FISH confirms copy number alterations in d by showing MYC amplification as multiple scattered signals and two copies of the chromosome 8 in a representative tumour cell nucleus. (Green—fluorescently labelled BAC RP11-367L7—MYC gene region; Red—centromeric region of chromosome 8—CHR8-10-RE). Scale bar, 10 μm. Supplementary Figures 11 and 12 are full images of gel and FISH presented in (f) and (g), respectively.
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Figure 2: Evidence of chromothripsis in EAC tumours(a) Circos plot of tumour OESO_1527 containing copy number and BAF 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. Circos plot37 shows a high concentration of SVs on chromosome 9. (b) Zoomed-in view of events on chromosome 9 of tumour OESO_1527 showing evidence of chromosome shattering (chromothripsis). From top to bottom, graphs show SVs, copy number, logR ratio and BAF. There are changes in copy number state, concentration of a high number of SVs and retention of heterozygosity. (c) The genome distribution of somatic SVs for tumour OESO_3213. Circos plot containing copy number and SVs shows a concentration of events on chromosome 8. (d) Zoomed-in view of events on chromosome 8 in OESO_3213 showing SVs, copy number, logR ratio and B-allele frequency. (e) Inferred double-minute chromosome (DM) harbouring MYC oncogene. Blue blocks show fragments of chromosome 8 inferred to form DM and green block shows position of FISH probe. (f) Agarose gel showing PCR verification of SV events inferred to contribute to the DM. T, tumour, N, adjacent normal esophagus, numbers indicate SVs as shown in e. (g) FISH confirms copy number alterations in d by showing MYC amplification as multiple scattered signals and two copies of the chromosome 8 in a representative tumour cell nucleus. (Green—fluorescently labelled BAC RP11-367L7—MYC gene region; Red—centromeric region of chromosome 8—CHR8-10-RE). Scale bar, 10 μm. Supplementary Figures 11 and 12 are full images of gel and FISH presented in (f) and (g), respectively.
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