Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis

Nones, K. et al. (2014) Genomic catastrophes frequently arise in esophageal adenocarcinoma and drive tumorigenesis. Nature Communications, 5, 5224. (doi: 10.1038/ncomms6224) (PMID:25351503) (PMCID:PMC4596003)

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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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Bailey, Dr Peter and Grimmond, Professor Sean
Authors: Nones, 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., Bruxner, T. J.C., Christ, A. N., Harliwong, I., Nourse, C., Nourbakhsh, E., Anderson, M., Kazakoff, S., Leonard, C., Wood, S., Simpson, P. T., Reid, L. E., Krause, L., Hussey, D. J., Watson, D. I., Lord, R. V., Nancarrow, D., Phillips, W. A., Gotley, D., Smithers, B. M., Whiteman, D. C., Hayward, N. K., Campbell, P. J., Pearson, J. V., Grimmond, S. M., and Barbour, A. P.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Nature Communications
Publisher:Nature Publishing Group
ISSN:2041-1723
ISSN (Online):2041-1723
Copyright Holders:Copyright © 2014 Macmillan Publishers Limited
First Published:First published in Nature Communications 5:5224
Publisher Policy:Reproduced under a Creative Commons License

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