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Nat Commun. 2014 Oct 29;5:5224. doi: 10.1038/ncomms6224.

Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis.

Author information

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.
3
Surgical Oncology Group, School of Medicine, The University of Queensland, Translational Research Institute at the Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia.
4
Department of Anatomical Pathology, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia.
5
The University of Queensland, UQ Centre for Clinical Research, Herston, Brisbane, Queensland 4029, Australia.
6
The University of Queensland, School of Medicine, Herston, Queensland 4006, Australia.
7
Flinders University Department of Surgery, Flinders Medical Centre, Bedford Park, South Australia 5042, Australia.
8
St Vincent's Centre for Applied Medical Research, University of Notre Dame and University of New South Wales, Sydney, New South Wales 2011, Australia.
9
Cancer Research Division, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
10
Department of Surgery, School of Medicine, The University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland 4102, Australia.
11
Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK.
12
Wolfson Wohl Cancer Research Centre, Institute for Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
#
Contributed equally

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.

PMID:
25351503
PMCID:
PMC4596003
DOI:
10.1038/ncomms6224
[Indexed for MEDLINE]
Free PMC Article

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