Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma

Sujath Abbas, Oriol Pich, Ginny Devonshire, Shahriar A. Zamani, Annalise Katz-Summercorn, Sarah Killcoyne, Calvin Cheah, Barbara Nutzinger, Nicola Grehan, Nuria Lopez-Bigas, Rebecca C. Fitzgerald () and Maria Secrier ()
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Sujath Abbas: University of Cambridge
Oriol Pich: The Barcelona Institute of Science and Technology
Ginny Devonshire: University of Cambridge
Shahriar A. Zamani: University of Cambridge
Annalise Katz-Summercorn: University of Cambridge
Sarah Killcoyne: University of Cambridge
Calvin Cheah: University of Cambridge
Barbara Nutzinger: University of Cambridge
Nicola Grehan: University of Cambridge
Nuria Lopez-Bigas: The Barcelona Institute of Science and Technology
Rebecca C. Fitzgerald: University of Cambridge
Maria Secrier: University College London

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract A variety of mutational processes drive cancer development, but their dynamics across the entire disease spectrum from pre-cancerous to advanced neoplasia are poorly understood. We explore the mutagenic processes shaping oesophageal adenocarcinoma tumorigenesis in 997 instances comprising distinct stages of this malignancy, from Barrett Oesophagus to primary tumours and advanced metastatic disease. The mutational landscape is dominated by the C[T > C/G]T substitution enriched signatures SBS17a/b, which are linked with TP53 mutations, increased proliferation, genomic instability and disease progression. The APOBEC mutagenesis signature is a weak but persistent signal amplified in primary tumours. We also identify prevalent alterations in DNA damage repair pathways, with homologous recombination, base and nucleotide excision repair and translesion synthesis mutated in up to 50% of the cohort, and surprisingly uncoupled from transcriptional activity. Among these, the presence of base excision repair deficiencies show remarkably poor prognosis in the cohort. In this work, we provide insights on the mutational aetiology and changes enabling the transition from pre-neoplastic to advanced oesophageal adenocarcinoma.

Date: 2023
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DOI: 10.1038/s41467-023-39957-6

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