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Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance (vol 48, pg 1131, 2016)

Accepted version
Peer-reviewed

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Type

Article

Change log

Authors

Secrier, Maria 
Li, Xiaodun 
de Silva, Nadeera 
Eldridge, Matthew D 
Contino, Gianmarco 

Abstract

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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Keywords

Journal Title

NATURE GENETICS

Conference Name

Journal ISSN

1061-4036
1546-1718

Volume Title

49

Publisher

Sponsorship
Cancer Research UK (CB4160)
Cancer Research UK (C14303/A17197)
Cancer Research Uk (None)