Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis

Katia Nones, Nicola Waddell, Nicola Wayte, Ann-Marie Patch, Peter Bailey, Felicity Newell, Oliver Holmes, Jürgen Fink, Michael Quinn, Yue Tang, Guy Lampe, Kelly Quek, Kelly Loffler, Suzanne Manning, Senel Idrisoglu, David Miller, Qinying Xu, Nick Waddell, Peter Wilson, Timothy BruxnerAngelika Christ, Ivon Harliwong, Craig Nourse, Ehsan Nourbakhsh, Matthew Anderson, Stephen Kazakoff, Conrad Leonard, Scott Wood, Peter Simpson, Lynne Reid, Lutz Krause, Damian Hussey, David Watson, Reginald Lord, Derek Nancarrow, Wayne Phillips, David Gotley, B Smithers, David Whiteman, Nicholas Hayward, Peter Campbell, John Pearson, Sean Grimmond, Andrew Barbour

    Research output: Contribution to journalArticlepeer-review

    196 Citations (Scopus)

    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.

    Original languageEnglish
    Article number5224
    Pages (from-to)Art 5224
    JournalNature Communications
    Volume5
    DOIs
    Publication statusPublished - 2014

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