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Secrier, Maria and Li, Xiaodun and de Silva, Nadeera and Eldridge, Matthew D. and Contino, Gianmarco and Bornschein, Jan and MacRae, Shona and Grehan, Nicola and O'Donovan, Maria and Miremadi, Ahmad and Yang, Tsun-Po and Bower, Lawrence and Chettouh, Hamza and Crawte, Jason and Galeano-Dalmau, Núria and Grabowska, Anna and Saunders, John and Underwood, Tim and Waddell, Nicola and Barbour, Andrew P. and Nutzinger, Barbara and Achilleos, Achilleas and Edwards, Paul A.W. and Lynch, Andy G. and Tavaré, Simon and Fitzgerald, Rebecca C. and Noorani, Ayesha and Elliott, Rachael Fels and Weaver, Jamie and Ross-Innes, Caryn and Smith, Laura and Abdullahi, Zarah and de la Rue, Rachel and Cluroe, Alison and Malhotra, Shalini and Hardwick, Richard and Ford, Hugo and Smith, Mike L. and Davies, Jim and Turkington, Richard and Hayes, Stephen J. and Ang, Yeng and Preston, Shaun R. and Oakes, Sarah and Bagwan, Izhar and Save, Vicki and Skipworth, Richard J.E. and Hupp, Ted R. and O'Neill, J. Robert and Tucker, Olga and Taniere, Philippe and Noble, Fergus and Owsley, Jack and Lovat, Laurence and Haidry, Rehan and Eneh, Victor and Crichton, Charles and Barr, Hugh and Shepherd, Neil and Old, Oliver and Lagergren, Jesper and Gossage, James and Davies, Andrew and Chang, Fuju and Zylstra, Janine and Sanders, Grant and Berrisford, Richard and Harden, Catherine and Bunting, David and Lewis, Mike and Cheong, Ed and Kumar, Bhaskar and Parsons, Simon L. and Soomro, Irshad and Kaye, Philip and Collier, Pamela and Igali, Laszlo and Welch, Ian and Scott, Michael and Sothi, Shamila and Suortamo, Sari and Lishman, Suzy and Beardsmore, Duncan and Francies, Hayley E. and Garnett, Mathew J. and Pearson, John V. and Nones, Katia and Patch, Ann-Marie and Grimmond, Sean M. (2016) Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance. Nature Genetics, 48 (10). pp. 1131-1141. ISSN 1546-1718

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.

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