Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis
AuthorNones, K; Waddell, N; Wayte, N; Patch, A-M; Bailey, P; Newell, F; Holmes, O; Fink, JL; Quinn, MCJ; Tang, YH; ...
Source TitleNature Communications
PublisherNATURE PUBLISHING GROUP
AffiliationCentre for Cancer Research
Sir Peter MacCallum Department of Oncology
Document TypeJournal Article
CitationsNones, K., Waddell, N., Wayte, N., Patch, A. -M., Bailey, P., Newell, F., Holmes, O., Fink, J. L., Quinn, M. C. J., Tang, Y. H., Lampe, G., Quek, K., Loffler, K. A., Manning, S., Idrisoglu, S., Miller, D., Xu, Q., Waddell, N., Wilson, P. J. ,... Barbour, A. P. (2014). Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis. NATURE COMMUNICATIONS, 5 (1), https://doi.org/10.1038/ncomms6224.
Access StatusOpen Access
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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