Mutational signatures reveal subgroups of distinct aetiology and new therapeutic opportunities in oesophageal adenocarcinoma


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Maria Secrier1
1Cancer Research UK Cambridge Institute, University of Cambridge

Abstract

Oesophageal adenocarcinoma has increased rapidly in the western world, but the underlying causes and the mutational processes that contribute to this cancer are still unclear. Due to the lack of robust classification methods, targeted therapy trials have so far been disappointing. We sought to investigate the aetiology and sub-classification of oesophageal adenocarcinoma by characterising the mutational patterns in the genomes of 129 chemo-naïve patients for which whole-genome sequencing data was available.

Mutational signatures reveal three distinct molecular subtypes with potential therapeutic relevance, verified in an independent cohort of 87 samples: i) ‘DNA Damage Repair (DDR) impaired’ - enriched for BRCA signature with prevalent defects in the homologous recombination pathway; ii) ‘Mutagenic’ - dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; iii) ‘C>A/T dominant’ - with evidence of an ageing imprint. Further analysis and experimental validation suggests that PARP inhibitors may be effective in the HR-scarred tumours of the ‘DDR impaired’ subgroup, while combination therapy targeting ERBB2/MET could be further investigated in the ‘C>A/T dominant’ subgroup. The ‘mutagenic’ subgroup appears to be linked to gastric acid exposure, and its genomic features, as well as higher CD8+ T-cell densities in these tumours suggest an increased immunogenic potential.

In summary, mutational signatures have not only uncovered three subgroups of oesophageal adenocarcinoma with clear aetiological differences, but could also be used as a high-throughput, spatially unbiased stratification strategy in the clinic, to inform treatment options for this cancer.