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.
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
Maria
M
Secrier
Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
Xiaodun
X
Li
Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
Nadeera
N
de Silva
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
Matthew D
MD
Eldridge
Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
Gianmarco
G
Contino
Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
Jan
J
Bornschein
Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
Shona
S
MacRae
Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
Nicola
N
Grehan
Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.|Department of Histopathology, Cambridge University Hospital NHS Trust, Cambridge, UK.
Maria
M
O'Donovan
Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.|Department of Histopathology, Cambridge University Hospital NHS Trust, Cambridge, UK.
Ahmad
A
Miremadi
Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
Tsun-Po
TP
Yang
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
Lawrence
L
Bower
Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
Hamza
H
Chettouh
Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
Jason
J
Crawte
Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
Núria
N
Galeano-Dalmau
Queen's Medical Centre, University of Nottingham, Nottingham, UK.
Anna
A
Grabowska
Department of Oesophagogastric Surgery, Nottingham University Hospitals NHS Trust, Nottingham, UK.
John
J
Saunders
Cancer Sciences Division, University of Southampton, Southampton, UK.|University Hospital Southampton NHS Foundation Trust, Southampton, UK.
Tim
T
Underwood
Department of Genetics and Computational Biology, QIMR Berghofer, Herston, Queensland, Australia.
Nicola
N
Waddell
Surgical Oncology Group, School of Medicine, University of Queensland, Translational Research Institute at the Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland, Australia.|Department of Surgery, School of Medicine, University of Queensland, Princess Alexandra Hospital, Woolloongabba, Brisbane, Queensland, Australia.
Andrew P
AP
Barbour
Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
Barbara
B
Nutzinger
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
Achilleas
0000-0001-7157-8991
A
Achilleos
Department of Pathology, University of Cambridge, Cambridge, UK.
Paul A W
PA
Edwards
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
Andy G
AG
Lynch
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
Simon
S
Tavaré
Medical Research Council Cancer Unit, Hutchison/Medical Research Council Research Centre, University of Cambridge, Cambridge, UK.
Rebecca C
RC
Fitzgerald
D000230:Adenocarcinoma / Q000145:classification / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D016827:CD8 Antigens / Q000276:immunology; D045744:Cell Line, Tumor; D015331:Cohort Studies; D004249:DNA Damage; D004273:DNA, Neoplasm; D004938:Esophageal Neoplasms / Q000145:classification / Q000235:genetics* / Q000276:immunology / Q000628:therapy; D005260:Female; D018740:Genetic Heterogeneity; D015894:Genome, Human; D006801:Humans; D008297:Male; D009154:Mutation; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D017422:Sequence Analysis, DNA
D000970:Antineoplastic Agents; D016827:CD8 Antigens; D004273:DNA, Neoplasm; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D020794:Receptor Protein-Tyrosine Kinases