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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.

Original publication

DOI

10.1038/ng.3659

Type

Journal article

Journal

Nature genetics

Publication Date

10/2016

Volume

48

Pages

1131 - 1141

Addresses

Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.

Keywords

Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS) Consortium, Cell Line, Tumor, Humans, Adenocarcinoma, Esophageal Neoplasms, DNA Damage, Receptor Protein-Tyrosine Kinases, DNA, Neoplasm, Antineoplastic Agents, Cohort Studies, Sequence Analysis, DNA, Genetic Heterogeneity, Mutation, Genome, Human, Aged, Female, Male, Poly(ADP-ribose) Polymerase Inhibitors, CD8 Antigens