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

description: 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 &gt; 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.