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

Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance
Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance
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.
1061-4036
1131-1141
Secrier, Maria
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Li, Xiaodun
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de Silva, Nadeera
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Eldridge, Matthew D.
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Contino, Gianmarco
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Bornschein, Jan
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MacRae, Shona
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Grehan, Nicola
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O'Donovan, Maria
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Miremadi, Ahmad
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Yang, Tsun-Po
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Bower, Lawrence
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Chettouh, Hamza
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Crawte, Jason
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Galeano-Dalmau, Nuria
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Grabowska, Anna
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Saunders, John
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Underwood, Tim
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Waddell, Nicola
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Barbour, Andrew P.
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Nutzinger, Barbara
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Achilleos, Achilleas
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Edwards, Paul A.W.
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Lynch, Andy G.
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Tavare, Simon
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Fitzgerald, Rebecca C.
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Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium
Secrier, Maria
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Li, Xiaodun
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de Silva, Nadeera
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Eldridge, Matthew D.
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Contino, Gianmarco
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Bornschein, Jan
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MacRae, Shona
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Grehan, Nicola
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O'Donovan, Maria
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Miremadi, Ahmad
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Yang, Tsun-Po
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Bower, Lawrence
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Chettouh, Hamza
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Crawte, Jason
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Galeano-Dalmau, Nuria
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Grabowska, Anna
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Saunders, John
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Underwood, Tim
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Waddell, Nicola
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Barbour, Andrew P.
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Nutzinger, Barbara
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Achilleos, Achilleas
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Edwards, Paul A.W.
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Lynch, Andy G.
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Tavare, Simon
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Fitzgerald, Rebecca C.
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Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium (2016) Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance. Nature Genetics, 48 (10), 1131-1141. (doi:10.1038/ng.3659).

Record type: Article

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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Manuscript_NG-A42719R_accepted.docx - Accepted Manuscript
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Accepted/In Press date: 21 June 2016
e-pub ahead of print date: 5 September 2016
Published date: October 2016
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 397159
URI: http://eprints.soton.ac.uk/id/eprint/397159
ISSN: 1061-4036
PURE UUID: 2b541f53-86a2-4362-b451-a4c0a01b3dfe
ORCID for Tim Underwood: ORCID iD orcid.org/0000-0001-9455-2188

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Date deposited: 29 Jun 2016 12:43
Last modified: 15 Mar 2024 05:41

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Contributors

Author: Maria Secrier
Author: Xiaodun Li
Author: Nadeera de Silva
Author: Matthew D. Eldridge
Author: Gianmarco Contino
Author: Jan Bornschein
Author: Shona MacRae
Author: Nicola Grehan
Author: Maria O'Donovan
Author: Ahmad Miremadi
Author: Tsun-Po Yang
Author: Lawrence Bower
Author: Hamza Chettouh
Author: Jason Crawte
Author: Nuria Galeano-Dalmau
Author: Anna Grabowska
Author: John Saunders
Author: Tim Underwood ORCID iD
Author: Nicola Waddell
Author: Andrew P. Barbour
Author: Barbara Nutzinger
Author: Achilleas Achilleos
Author: Paul A.W. Edwards
Author: Andy G. Lynch
Author: Simon Tavare
Author: Rebecca C. Fitzgerald
Corporate Author: Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium

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