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Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma

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journal contribution
posted on 2023-07-25, 12:50 authored by Sujath Abbas, Oriol Pich, Ginny Devonshire, Shahriar A Zamani, Annalise Katz-Summercorn, Sarah Killcoyne, Calvin Cheah, Barbara Nutzinger, Nicola Grehan, Nuria Lopez-Bigas, Paul AW Edwards, Elwira Fidziukiewicz, Aisling M Redmond, Adam Freeman, Elizabeth C Smyth, Maria O’Donovan, Ahmad Miremadi, Shalini Malhotra, Monika Tripathi, Hannah Coles, Conor Flint, Matthew Eldridge, Sriganesh Jammula, Jim Davies, Charles Crichton, Nick Carroll, Richard H Hardwick, Peter Safranek, Andrew Hindmarsh, Vijayendran Sujendran, Stephen J Hayes, Yeng Ang, Andrew Sharrocks, Shaun R Preston, Izhar Bagwan, Vicki Save, Richard JE Skipworth, Ted R Hupp, J Robert O’Neill, Olga Tucker, Andrew Beggs, Philippe Taniere, Sonia Puig, Gianmarco Contino, Timothy J Underwood, Robert C Walker, Ben L Grace, Jesper Lagergren, James Gossage, Andrew Davies, Fuju Chang, Ula Mahadeva, Vicky Goh, Francesca D Ciccarelli, Grant Sanders, Richard Berrisford, David Chan, Ed Cheong, Bhaskar Kumar, L Sreedharan, Simon L Parsons, Irshad Soomro, Philip Kaye, John Saunders, Laurence Lovat, Rehan Haidry, Michael Scott, Sharmila Sothi, Suzy Lishman, George B Hanna, Christopher J Peters, Krishna Moorthy, Anna Grabowska, Richard Turkington, Damian McManus, Helen Coleman, Russell D Petty, Freddie Bartlett, Rebecca C Fitzgerald, Maria Secrier
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.


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