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Nat Genet. 2016 Oct;48(10):1131-41. doi: 10.1038/ng.3659. Epub 2016 Sep 5.

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

Author information

1
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
2
Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
3
Department of Histopathology, Cambridge University Hospital NHS Trust, Cambridge, UK.
4
Queen's Medical Centre, University of Nottingham, Nottingham, UK.
5
Department of Oesophagogastric Surgery, Nottingham University Hospitals NHS Trust, Nottingham, UK.
6
Cancer Sciences Division, University of Southampton, Southampton, UK.
7
University Hospital Southampton NHS Foundation Trust, Southampton, UK.
8
Department of Genetics and Computational Biology, QIMR Berghofer, Herston, Queensland, Australia.
9
Surgical Oncology Group, School of Medicine, University of Queensland, Translational Research Institute at the Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland, Australia.
10
Department of Surgery, School of Medicine, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland, Australia.
11
Department of Pathology, University of Cambridge, Cambridge, UK.

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.

PMID:
27595477
PMCID:
PMC5957269
DOI:
10.1038/ng.3659
[Indexed for MEDLINE]
Free PMC Article

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