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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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Mutational signatures found in EAC(a) Five mutational signatures were detected in EAC. Each signature is represented by the proportion of somatic substitutions (C>A, C>G, C>T, T>A, T>C and T>G). Substitutions are displayed in a trinucleotide context (including information about the bases immediately 3′ and 5′ to the mutated base) resulting in 96 potential contexts. (b) Contribution of mutational signatures operative in individual tumours. Each bar represents a tumour and the y axis represents the contribution of each signature within tumours, shown as number of mutations per Mb. The BRCA, the unknown and APOBEC signatures were most prevalent only in one tumour each (BRCA contributed ~57% of OESO_1636 mutations and unknown signature represents 67% of OESO_0303 mutations). The APOBEC signature, previously described in EAC and other tumour types11, contributes to more than 50% of the mutations in tumour OESO_1154, with small contributions in other samples. The age signature, previously described in EAC, is the second major operative mutational processes in this cohort. The signature characterized by T>G at TTsites is the most prominent within this cohort, representing ≥40% of mutations in 10 of 22 tumours (Supplementary Fig. 1).
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Figure 1: Mutational signatures found in EAC(a) Five mutational signatures were detected in EAC. Each signature is represented by the proportion of somatic substitutions (C>A, C>G, C>T, T>A, T>C and T>G). Substitutions are displayed in a trinucleotide context (including information about the bases immediately 3′ and 5′ to the mutated base) resulting in 96 potential contexts. (b) Contribution of mutational signatures operative in individual tumours. Each bar represents a tumour and the y axis represents the contribution of each signature within tumours, shown as number of mutations per Mb. The BRCA, the unknown and APOBEC signatures were most prevalent only in one tumour each (BRCA contributed ~57% of OESO_1636 mutations and unknown signature represents 67% of OESO_0303 mutations). The APOBEC signature, previously described in EAC and other tumour types11, contributes to more than 50% of the mutations in tumour OESO_1154, with small contributions in other samples. The age signature, previously described in EAC, is the second major operative mutational processes in this cohort. The signature characterized by T>G at TTsites is the most prominent within this cohort, representing ≥40% of mutations in 10 of 22 tumours (Supplementary Fig. 1).

Mentions: Mutation spectral analysis confirmed that EACs display a preponderance of C>T transitions in coding sequences and T>G transversions across the genome3,17 (Supplementary Data 7). The sequence context of mutations can reveal mutational processes or signatures within tumours11. Three recently reported EAC mutational signatures11 were also detected here: Age signature (driven by general deamination), APOBEC signature and T>G mutations at TT sites. In addition, the BRCA-deficiency signature previously reported only in breast, ovarian and pancreatic tumours11 and an unknown signature were also observed (Fig. 1a). The signature characterized by T>G mutations at TT sites was the most prominent process within the cohort (Fig. 1b) and tumours with high contribution of this signature showed a trend towards poor survival (Supplementary Fig. 1). Strand bias was observed only for the signature characterized by T>G mutations at TT sites (Supplementary Fig. 2). T>G mutations at TT sites have been proposed to arise from oxidative DNA damage3. Reflux of gastric and bile acids which are risk factors for BE and EAC, have been associated with oxidative stress and oxidative DNA damage18. Furthermore incubation of BE tissues with a low pH bile acid cocktail leads to increased formation of 8-OH-dG18, which was suggested to be associated with T>G mutations at TT sites19,20. This might indicate a mechanism underlying this mutational signature that needs further investigation.


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)

Mutational signatures found in EAC(a) Five mutational signatures were detected in EAC. Each signature is represented by the proportion of somatic substitutions (C>A, C>G, C>T, T>A, T>C and T>G). Substitutions are displayed in a trinucleotide context (including information about the bases immediately 3′ and 5′ to the mutated base) resulting in 96 potential contexts. (b) Contribution of mutational signatures operative in individual tumours. Each bar represents a tumour and the y axis represents the contribution of each signature within tumours, shown as number of mutations per Mb. The BRCA, the unknown and APOBEC signatures were most prevalent only in one tumour each (BRCA contributed ~57% of OESO_1636 mutations and unknown signature represents 67% of OESO_0303 mutations). The APOBEC signature, previously described in EAC and other tumour types11, contributes to more than 50% of the mutations in tumour OESO_1154, with small contributions in other samples. The age signature, previously described in EAC, is the second major operative mutational processes in this cohort. The signature characterized by T>G at TTsites is the most prominent within this cohort, representing ≥40% of mutations in 10 of 22 tumours (Supplementary Fig. 1).
© Copyright Policy - permissions-link - open-access
Related In: Results  -  Collection

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

Figure 1: Mutational signatures found in EAC(a) Five mutational signatures were detected in EAC. Each signature is represented by the proportion of somatic substitutions (C>A, C>G, C>T, T>A, T>C and T>G). Substitutions are displayed in a trinucleotide context (including information about the bases immediately 3′ and 5′ to the mutated base) resulting in 96 potential contexts. (b) Contribution of mutational signatures operative in individual tumours. Each bar represents a tumour and the y axis represents the contribution of each signature within tumours, shown as number of mutations per Mb. The BRCA, the unknown and APOBEC signatures were most prevalent only in one tumour each (BRCA contributed ~57% of OESO_1636 mutations and unknown signature represents 67% of OESO_0303 mutations). The APOBEC signature, previously described in EAC and other tumour types11, contributes to more than 50% of the mutations in tumour OESO_1154, with small contributions in other samples. The age signature, previously described in EAC, is the second major operative mutational processes in this cohort. The signature characterized by T>G at TTsites is the most prominent within this cohort, representing ≥40% of mutations in 10 of 22 tumours (Supplementary Fig. 1).
Mentions: Mutation spectral analysis confirmed that EACs display a preponderance of C>T transitions in coding sequences and T>G transversions across the genome3,17 (Supplementary Data 7). The sequence context of mutations can reveal mutational processes or signatures within tumours11. Three recently reported EAC mutational signatures11 were also detected here: Age signature (driven by general deamination), APOBEC signature and T>G mutations at TT sites. In addition, the BRCA-deficiency signature previously reported only in breast, ovarian and pancreatic tumours11 and an unknown signature were also observed (Fig. 1a). The signature characterized by T>G mutations at TT sites was the most prominent process within the cohort (Fig. 1b) and tumours with high contribution of this signature showed a trend towards poor survival (Supplementary Fig. 1). Strand bias was observed only for the signature characterized by T>G mutations at TT sites (Supplementary Fig. 2). T>G mutations at TT sites have been proposed to arise from oxidative DNA damage3. Reflux of gastric and bile acids which are risk factors for BE and EAC, have been associated with oxidative stress and oxidative DNA damage18. Furthermore incubation of BE tissues with a low pH bile acid cocktail leads to increased formation of 8-OH-dG18, which was suggested to be associated with T>G mutations at TT sites19,20. This might indicate a mechanism underlying this mutational signature that needs further investigation.

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