Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance

Secrier, Maria; Li, Xiaodun; de Silva, Nadeera; Eldridge, Matthew D.; Contino, Gianmarco; Bornschein, Jan; MacRae, Shona; Grehan, Nicola; O'Donovan, Maria; Miremadi, Ahmad; Yang, Tsun-Po; Bower, Lawrence; Chettouh, Hamza; Crawte, Jason; Galeano-Dalmau, N?ria; Grabowska, Anna; Saunders, John; Underwood, Tim; Waddell, Nicola; Barbour, Andrew P.; Nutzinger, Barbara; Achilleos, Achilleas; Edwards, Paul A.W.; Lynch, Andy G.; Tavar?, Simon; Fitzgerald, Rebecca C.; Noorani, Ayesha; Elliott, Rachael Fels; Weaver, Jamie; Ross-Innes, Caryn; Smith, Laura; Abdullahi, Zarah; de la Rue, Rachel; Cluroe, Alison; Malhotra, Shalini; Hardwick, Richard; Ford, Hugo; Smith, Mike L.; Davies, Jim; Turkington, Richard; Hayes, Stephen J.; Ang, Yeng; Preston, Shaun R.; Oakes, Sarah; Bagwan, Izhar; Save, Vicki; Skipworth, Richard J.E.; Hupp, Ted R.; O'Neill, J. Robert; Tucker, Olga; Taniere, Philippe; Noble, Fergus; Owsley, Jack; Lovat, Laurence; Haidry, Rehan; Eneh, Victor; Crichton, Charles; Barr, Hugh; Shepher...

Abstract

Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing owing to a lack of robust stratification methods. Whole-genome sequencing (WGS) analysis of 129 cases demonstrated that this is a heterogeneous cancer dominated by copy number alterations with frequent large-scale rearrangements. Co-amplification of receptor tyrosine kinases (RTKs) and/or downstream mitogenic activation is almost ubiquitous; thus tailored combination RTK inhibitor (RTKi) therapy might be required, as we demonstrate in vitro. However, mutational signatures showed three distinct molecular subtypes with potential therapeutic relevance, which we verified in an independent cohort (n = 87): (i) enrichment for BRCA signature with prevalent defects in the homologous recombination pathway; (ii) dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; and (iii) C>A/T mutational pattern with evidence of an aging imprint. These subtypes could be ascertained using a clinically applicable sequencing strategy (low coverage) as a basis for therapy selection.

Citation

Secrier, M., Li, X., de Silva, N., Eldridge, M. D., Contino, G., Bornschein, J., MacRae, S., Grehan, N., O'Donovan, M., Miremadi, A., Yang, T.-P., Bower, L., Chettouh, H., Crawte, J., Galeano-Dalmau, N., Grabowska, A., Saunders, J., Underwood, T., Waddell, N., Barbour, A. P., …Grimmond, S. M. (2016). Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance. Nature Genetics, 48(10), https://doi.org/10.1038/ng.3659

• Journal Article Type: Article
• Acceptance Date: Aug 5, 2016
• Online Publication Date: Sep 5, 2016
• Publication Date: Oct 31, 2016
• Deposit Date: Feb 9, 2017
• Publicly Available Date: Feb 9, 2017
• Journal: Nature Genetics
• Print ISSN: 1061-4036
• Electronic ISSN: 1546-1718
• Publisher: Nature Publishing Group
• Peer Reviewed: Peer Reviewed
• Volume: 48
• Issue: 10
• DOI: https://doi.org/10.1038/ng.3659
• Keywords: DNA sequencing, Genetics research, Oesophageal cancer
• Public URL: https://nottingham-repository.worktribe.com/output/820655
• Publisher URL: http://dx.doi.org/10.1038/ng.3659
• Contract Date: Feb 9, 2017