title: Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis.
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.
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.|QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.
authors.forename: Katia
authors.initials: K
authors.lastname: Nones
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.|QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.
authors.forename: Nicola
authors.initials: N
authors.lastname: Waddell
authors.affiliation: Surgical Oncology Group, School of Medicine, The University of Queensland, Translational Research Institute at the Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia.
authors.forename: Nicci
authors.initials: N
authors.lastname: Wayte
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Patch
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Bailey
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Felicity
authors.initials: F
authors.lastname: Newell
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.|QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.
authors.forename: Oliver
authors.initials: O
authors.lastname: Holmes
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: J Lynn
authors.initials: JL
authors.lastname: Fink
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Michael C J
authors.initials: MCJ
authors.lastname: Quinn
authors.affiliation: Surgical Oncology Group, School of Medicine, The University of Queensland, Translational Research Institute at the Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia.
authors.forename: Yue Hang
authors.initials: YH
authors.lastname: Tang
authors.affiliation: Department of Anatomical Pathology, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia.
authors.forename: Guy
authors.initials: G
authors.lastname: Lampe
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Kelly
authors.initials: K
authors.lastname: Quek
authors.affiliation: Surgical Oncology Group, School of Medicine, The University of Queensland, Translational Research Institute at the Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Loffler
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Manning
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Senel
authors.initials: S
authors.lastname: Idrisoglu
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Miller
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.|QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.
authors.forename: Qinying
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Nick
authors.initials: N
authors.lastname: Waddell
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wilson
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Timothy J C
authors.initials: TJC
authors.lastname: Bruxner
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Angelika N
authors.initials: AN
authors.lastname: Christ
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Ivon
authors.initials: I
authors.lastname: Harliwong
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Craig
authors.initials: C
authors.lastname: Nourse
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Nourbakhsh
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Anderson
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Kazakoff
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.|QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.
authors.forename: Conrad
authors.initials: C
authors.lastname: Leonard
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.|QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.
authors.forename: Scott
authors.initials: S
authors.lastname: Wood
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.|The University of Queensland, UQ Centre for Clinical Research, Herston, Brisbane, Queensland 4029, Australia.|The University of Queensland, School of Medicine, Herston, Queensland 4006, Australia.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Simpson
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.|The University of Queensland, UQ Centre for Clinical Research, Herston, Brisbane, Queensland 4029, Australia.
authors.forename: Lynne E
authors.initials: LE
authors.lastname: Reid
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.
authors.forename: Lutz
authors.initials: L
authors.lastname: Krause
authors.affiliation: Flinders University Department of Surgery, Flinders Medical Centre, Bedford Park, South Australia 5042, Australia.
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Hussey
authors.affiliation: Flinders University Department of Surgery, Flinders Medical Centre, Bedford Park, South Australia 5042, Australia.
authors.forename: David I
authors.initials: DI
authors.lastname: Watson
authors.affiliation: St Vincent's Centre for Applied Medical Research, University of Notre Dame and University of New South Wales, Sydney, New South Wales 2011, Australia.
authors.forename: Reginald V
authors.initials: RV
authors.lastname: Lord
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.
authors.forename: Derek
authors.initials: D
authors.lastname: Nancarrow
authors.affiliation: Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Wayne A
authors.initials: WA
authors.lastname: Phillips
authors.affiliation: Department of Surgery, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Gotley
authors.affiliation: Department of Surgery, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia.
authors.forename: B Mark
authors.initials: BM
authors.lastname: Smithers
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.
authors.forename: David C
authors.initials: DC
authors.lastname: Whiteman
authors.affiliation: QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.
authors.forename: Nicholas K
authors.initials: NK
authors.lastname: Hayward
authors.affiliation: Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.|QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland 4006, Australia.
authors.forename: John V
authors.initials: JV
authors.lastname: Pearson
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.|Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Grimmond
authors.affiliation: Surgical Oncology Group, School of Medicine, The University of Queensland, Translational Research Institute at the Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia.|Department of Surgery, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Barbour
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology*; D063646:Carcinogenesis / Q000235:genetics* / Q000473:pathology; D019457:Chromosome Breakage; D002877:Chromosomes, Human / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000473:pathology*; D015321:Gene Rearrangement / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics