Data from a whole-genome sequencing analysis of 129 patients with oesophageal adenocarcinoma reveal the existence of three distinct molecular subtypes of this heterogeneous cancer: tumours enriched with BRCA mutations, with defective homologous recombination; those dominated by T>G mutations, with a high mutational load and neoantigen burden; and those with a C>A/T pattern of mutations, with evidence of an ageing imprint. These findings were confirmed using an independent validation cohort of 87 patients. Researchers tested the clinical relevance of these mutations in cell lines reflecting the characteristics of these three signature groups, and found that the BRCA mutation signature conferred greater sensitivity to poly [ADP-ribose] polymerase inhibition in combination with topotecan, while the T>G mutational signature conferred greater sensitivity to WEE1/CHK1 inhibition. These subtypes provide a basis for the selection of patient-specific treatment strategies.