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

• Published in: Nature genetics Vol. 48; no. 10; pp. 1131 - 1141
• Main Authors: Secrier, Maria, Li, Xiaodun, de Silva, Nadeera, Eldridge, Matthew D, Contino, Gianmarco, Bornschein, Jan, MacRae, Shona, Grehan, Nicola, O'Donovan, Maria, Miremadi, Ahmad, Yang, Tsun-Po, Bower, Lawrence, Chettouh, Hamza, Crawte, Jason, Galeano-Dalmau, Núria, Grabowska, Anna, Saunders, John, Underwood, Tim, Waddell, Nicola, Barbour, Andrew P, Nutzinger, Barbara, Achilleos, Achilleas, Edwards, Paul A W, Lynch, Andy G, Tavaré, Simon, Fitzgerald, Rebecca C
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.10.2016; Nature Publishing Group
• Subjects: 13/106; 13/51; 45; 45/23; 631/208/514/1948; 631/67/1504/1477; 692/308/2056; Adenocarcinoma; Adenocarcinoma - classification; Adenocarcinoma - genetics; Adenocarcinoma - immunology; Adenocarcinoma - therapy; Aged; Agriculture; Analysis; Animal Genetics and Genomics; Antineoplastic Agents - therapeutic use; Biomedical research; Biomedicine; Cancer; Cancer Research; Cancer therapies; CD8 Antigens - immunology; Cell adhesion & migration; Cell cycle; Cell Line, Tumor; Cohort Studies; Consortia; Crizotinib; DNA Damage; DNA, Neoplasm; Esophageal cancer; Esophageal Neoplasms - classification; Esophageal Neoplasms - genetics; Esophageal Neoplasms - immunology; Esophageal Neoplasms - therapy; Esophagus; Experiments; Female; Funding; Gene Function; Genetic aspects; Genetic Heterogeneity; Genome, Human; Genomes; Genomics; Health aspects; Hospitals; Human Genetics; Humans; Lapatinib; Male; Medical research; Mutation; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Receptor Protein-Tyrosine Kinases - antagonists & inhibitors; Receptor Protein-Tyrosine Kinases - metabolism; Sequence Analysis, DNA; Signal transduction; Tumor antigens; Tyrosine
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.3659

Rebecca Fitzgerald and colleagues report the whole-genome sequences of 129 esophageal adenocarcinomas, showing frequent copy number alterations and prevalent mutations in receptor tyrosine kinases concomitant with mitogenic activation. They further characterize mutation signatures and find three distinct molecular subtypes with potential for application to clinical diagnosis and treatment. 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.