Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis

Katia Nones, Nicola Waddell, Nicci Wayte, Ann-Marie Patch, Peter Bailey, Felicity Newell, Oliver Holmes, J. Lynn Fink, Michael C. J. Quinn, Yue Hang Tang, Guy Lampe, Kelly Quek, Kelly A. Loffler, Suzanne Manning, Senel Idrisoglu, David Miller, Qinying Xu, Nick Waddell, Peter J. Wilson, Timothy J. C. Bruxner, Angelika N. Christ, Ivon Harliwong, Craig Nourse, Ehsan Nourbakhsh, Matthew Anderson, Stephen Kazakoff, Conrad Leonard, Scott Wood, Peter T. Simpson, Lynne E. Reid, Lutz Krause, Damian J. Hussey, David I. Watson, Reginald V. Lord, Derek Nancarrow, Wayne A. Phillips, David Gotley, B. Mark Smithers, David C. Whiteman, Nicholas K. Hayward, Peter J. Campbell, John V. Pearson, Sean M. Grimmond () and Andrew P. Barbour ()
Additional contact information
Katia Nones: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Nicola Waddell: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Nicci Wayte: Surgical Oncology Group, School of Medicine, The University of Queensland, Translational Research Institute at the Princess Alexandra Hospital, Woolloongabba
Ann-Marie Patch: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Peter Bailey: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Felicity Newell: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Oliver Holmes: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
J. Lynn Fink: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Michael C. J. Quinn: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Yue Hang Tang: Surgical Oncology Group, School of Medicine, The University of Queensland, Translational Research Institute at the Princess Alexandra Hospital, Woolloongabba
Guy Lampe: Princess Alexandra Hospital, Woolloongabba
Kelly Quek: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Kelly A. Loffler: Surgical Oncology Group, School of Medicine, The University of Queensland, Translational Research Institute at the Princess Alexandra Hospital, Woolloongabba
Suzanne Manning: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Senel Idrisoglu: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
David Miller: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Qinying Xu: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Nick Waddell: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Peter J. Wilson: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Timothy J. C. Bruxner: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Angelika N. Christ: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Ivon Harliwong: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Craig Nourse: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Ehsan Nourbakhsh: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Matthew Anderson: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Stephen Kazakoff: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Conrad Leonard: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Scott Wood: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Peter T. Simpson: QIMR Berghofer Medical Research Institute, Herston
Lynne E. Reid: QIMR Berghofer Medical Research Institute, Herston
Lutz Krause: QIMR Berghofer Medical Research Institute, Herston
Damian J. Hussey: Flinders Medical Centre
David I. Watson: Flinders Medical Centre
Reginald V. Lord: St Vincent’s Centre for Applied Medical Research, University of Notre Dame and University of New South Wales
Derek Nancarrow: QIMR Berghofer Medical Research Institute, Herston
Wayne A. Phillips: Peter MacCallum Cancer Centre
David Gotley: School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba
B. Mark Smithers: School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba
David C. Whiteman: QIMR Berghofer Medical Research Institute, Herston
Nicholas K. Hayward: QIMR Berghofer Medical Research Institute, Herston
Peter J. Campbell: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton
John V. Pearson: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Sean M. Grimmond: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia
Andrew P. Barbour: Surgical Oncology Group, School of Medicine, The University of Queensland, Translational Research Institute at the Princess Alexandra Hospital, Woolloongabba

Nature Communications, 2014, vol. 5, issue 1, 1-9

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms6224

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