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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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Related in: MedlinePlus

Evidence of a chromothriptic event involving four chromosomes(a) Overview of the distribution of events in the genome of tumour OESO_0384. Circos plot of tumour OESO_0384 containing copy number and B-allele frequency (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) Detailed view of chromosomes 12, 13, 17 and 20 involved in the complex localized event. (c) Inferred DNA double-minute chromosome (DM) involving regions of chromosomes 12, 13 and 20. Red and green bars indicate location of FISH probes shown in e. (d) Agarose gel showing PCR verification of SV events inferred to be part of the DM in c. T, tumor, N, adjacent normal oesophagus, numbers indicate SVs as labelled in c. (e,f) FISH analysis demonstrated amplification of the two regions tested in representative tumour cell nuclei, plus the frequent colocalization of signals indicating fusion of regions of chromosomes 13 and 20 (see arrows for examples). Green—RP11-122N18 (chr13:78,416,550-78,591,831) to the EDNRB gene region, Red—RP11-192K14 (chr20:52,178,644-52,324,774). (g) FISH images show amplification and frequent colocalization of signals (see arrows for examples) indicating that chromosome regions of chr 13 and chr 12 are part of the inferred DM. FISH Green—RP11-122N18 (chr13:78,416,550-78,591,831) to EDNRB gene region and Red—RP11-77H17- (chr12:69,154,590-69,318,752) to MDM2 gene region. Scale bar, 10 μm. Supplementary figures 13 to 16 are full images of Figure 3(d) to (g).
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Figure 3: Evidence of a chromothriptic event involving four chromosomes(a) Overview of the distribution of events in the genome of tumour OESO_0384. Circos plot of tumour OESO_0384 containing copy number and B-allele frequency (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) Detailed view of chromosomes 12, 13, 17 and 20 involved in the complex localized event. (c) Inferred DNA double-minute chromosome (DM) involving regions of chromosomes 12, 13 and 20. Red and green bars indicate location of FISH probes shown in e. (d) Agarose gel showing PCR verification of SV events inferred to be part of the DM in c. T, tumor, N, adjacent normal oesophagus, numbers indicate SVs as labelled in c. (e,f) FISH analysis demonstrated amplification of the two regions tested in representative tumour cell nuclei, plus the frequent colocalization of signals indicating fusion of regions of chromosomes 13 and 20 (see arrows for examples). Green—RP11-122N18 (chr13:78,416,550-78,591,831) to the EDNRB gene region, Red—RP11-192K14 (chr20:52,178,644-52,324,774). (g) FISH images show amplification and frequent colocalization of signals (see arrows for examples) indicating that chromosome regions of chr 13 and chr 12 are part of the inferred DM. FISH Green—RP11-122N18 (chr13:78,416,550-78,591,831) to EDNRB gene region and Red—RP11-77H17- (chr12:69,154,590-69,318,752) to MDM2 gene region. Scale bar, 10 μm. Supplementary figures 13 to 16 are full images of Figure 3(d) to (g).

Mentions: The tumour OESO_3213 has evidence of a 2.5 Mb DM derived from shattering of chromosome 8 and random fusion of six fragments; one of which harbours the MYC oncogene. The SV events inferred to be involved in the DM were validated by PCR. FISH analysis confirmed that gene amplification is not due to homogenously staining regions but extra chromosomal amplification of MYC gene (Fig. 2). In a second tumour (OESO_0384), evidence of DM arising from a chromothriptic event involving four chromosomes harboured MDM2 gene was identified and similarly verified using PCR and FISH (Fig. 3). MDM2 is an oncogene and known inhibitor of TP53.


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 a chromothriptic event involving four chromosomes(a) Overview of the distribution of events in the genome of tumour OESO_0384. Circos plot of tumour OESO_0384 containing copy number and B-allele frequency (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) Detailed view of chromosomes 12, 13, 17 and 20 involved in the complex localized event. (c) Inferred DNA double-minute chromosome (DM) involving regions of chromosomes 12, 13 and 20. Red and green bars indicate location of FISH probes shown in e. (d) Agarose gel showing PCR verification of SV events inferred to be part of the DM in c. T, tumor, N, adjacent normal oesophagus, numbers indicate SVs as labelled in c. (e,f) FISH analysis demonstrated amplification of the two regions tested in representative tumour cell nuclei, plus the frequent colocalization of signals indicating fusion of regions of chromosomes 13 and 20 (see arrows for examples). Green—RP11-122N18 (chr13:78,416,550-78,591,831) to the EDNRB gene region, Red—RP11-192K14 (chr20:52,178,644-52,324,774). (g) FISH images show amplification and frequent colocalization of signals (see arrows for examples) indicating that chromosome regions of chr 13 and chr 12 are part of the inferred DM. FISH Green—RP11-122N18 (chr13:78,416,550-78,591,831) to EDNRB gene region and Red—RP11-77H17- (chr12:69,154,590-69,318,752) to MDM2 gene region. Scale bar, 10 μm. Supplementary figures 13 to 16 are full images of Figure 3(d) to (g).
© Copyright Policy - permissions-link - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 3: Evidence of a chromothriptic event involving four chromosomes(a) Overview of the distribution of events in the genome of tumour OESO_0384. Circos plot of tumour OESO_0384 containing copy number and B-allele frequency (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) Detailed view of chromosomes 12, 13, 17 and 20 involved in the complex localized event. (c) Inferred DNA double-minute chromosome (DM) involving regions of chromosomes 12, 13 and 20. Red and green bars indicate location of FISH probes shown in e. (d) Agarose gel showing PCR verification of SV events inferred to be part of the DM in c. T, tumor, N, adjacent normal oesophagus, numbers indicate SVs as labelled in c. (e,f) FISH analysis demonstrated amplification of the two regions tested in representative tumour cell nuclei, plus the frequent colocalization of signals indicating fusion of regions of chromosomes 13 and 20 (see arrows for examples). Green—RP11-122N18 (chr13:78,416,550-78,591,831) to the EDNRB gene region, Red—RP11-192K14 (chr20:52,178,644-52,324,774). (g) FISH images show amplification and frequent colocalization of signals (see arrows for examples) indicating that chromosome regions of chr 13 and chr 12 are part of the inferred DM. FISH Green—RP11-122N18 (chr13:78,416,550-78,591,831) to EDNRB gene region and Red—RP11-77H17- (chr12:69,154,590-69,318,752) to MDM2 gene region. Scale bar, 10 μm. Supplementary figures 13 to 16 are full images of Figure 3(d) to (g).
Mentions: The tumour OESO_3213 has evidence of a 2.5 Mb DM derived from shattering of chromosome 8 and random fusion of six fragments; one of which harbours the MYC oncogene. The SV events inferred to be involved in the DM were validated by PCR. FISH analysis confirmed that gene amplification is not due to homogenously staining regions but extra chromosomal amplification of MYC gene (Fig. 2). In a second tumour (OESO_0384), evidence of DM arising from a chromothriptic event involving four chromosomes harboured MDM2 gene was identified and similarly verified using PCR and FISH (Fig. 3). MDM2 is an oncogene and known inhibitor of TP53.

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