Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis

Kátia Nones(The University of Queensland), Nicola Waddell(The University of Queensland), Nicci Wayte(Translational Research Institute), Ann‐Marie Patch(The University of Queensland), Peter J. Bailey(The University of Queensland), Felicity Newell(The University of Queensland), Oliver Holmes(The University of Queensland), J. Lynn Fink(The University of Queensland), Michael C. Quinn(The University of Queensland), Yue Tang(Translational Research Institute), Guy Lampe(Princess Alexandra Hospital), Kelly Quek(The University of Queensland), Kelly A. Loffler(Translational Research Institute), Suzanne Manning(The University of Queensland), Senel Idrisoglu(The University of Queensland), David S. Miller(The University of Queensland), Qinying Xu(The University of Queensland), Nick M. Waddell(The University of Queensland), Peter J. Wilson(The University of Queensland), Timothy J. C. Bruxner(The University of Queensland), Angelika N. Christ(The University of Queensland), Ivon Harliwong(The University of Queensland), Craig Nourse(The University of Queensland), Ehsan Nourbakhsh(The University of Queensland), Matthew J. Anderson(The University of Queensland), Stephen H. Kazakoff(The University of Queensland), Conrad Leonard(The University of Queensland), Scott Wood(The University of Queensland), Peter T. Simpson(The University of Queensland), Lynne Reid(The University of Queensland), Lutz Krause(QIMR Berghofer Medical Research Institute), Damian J. Hussey(Flinders University), David I. Watson(Flinders University), Reginald V. Lord(UNSW Sydney), Derek J. Nancarrow(QIMR Berghofer Medical Research Institute), Wayne A. Phillips(Peter MacCallum Cancer Centre), D. C. Gotley(The University of Queensland), B. Mark Smithers(The University of Queensland), David C. Whiteman(QIMR Berghofer Medical Research Institute), Nicholas K. Hayward(QIMR Berghofer Medical Research Institute), Peter J. Campbell(Wellcome Sanger Institute), John V. Pearson(The University of Queensland), Sean M. Grimmond(The University of Queensland), Andrew P. Barbour(Translational Research Institute)
Nature Communications
October 29, 2014
10.1038/ncomms6224
Cited by 287Open Access
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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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