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; OCCAMS Consortium; Rebecca C. Fitzgerald; Maria Secrier

doi:10.1038/s41467-023-39957-6

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, OCCAMS Consortium, Rebecca C. Fitzgerald (Lead / Corresponding author), Maria Secrier (Lead / Corresponding author)

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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.

Original language	English
Article number	4239
Number of pages	16
Journal	Nature Communications
Volume	14
Issue number	1
Early online date	15 Jul 2023
DOIs	https://doi.org/10.1038/s41467-023-39957-6
Publication status	E-pub ahead of print - 15 Jul 2023

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-023-39957-6Licence: CC BY

Final published versionFinal published version, 5.13 MBLicence: CC BY

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Abbas, S., Pich, O., Devonshire, G., Zamani, S. A., Katz-Summercorn, A., Killcoyne, S., Cheah, C., Nutzinger, B., Grehan, N., Lopez-Bigas, N., OCCAMS Consortium, Fitzgerald, R. C., & Secrier, M. (2023). Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma. Nature Communications, 14(1), Article 4239. Advance online publication. https://doi.org/10.1038/s41467-023-39957-6

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title = "Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma",

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.",

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

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AU - Devonshire, Ginny

AU - Zamani, Shahriar A.

AU - Katz-Summercorn, Annalise

AU - Killcoyne, Sarah

AU - Cheah, Calvin

AU - Nutzinger, Barbara

AU - Grehan, Nicola

AU - Lopez-Bigas, Nuria

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AU - Kumar, Bhaskar

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AU - Parsons, Simon L.

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AU - Lovat, Laurence

AU - Haidry, Rehan

AU - Scott, Michael

AU - Sothi, Sharmila

AU - Lishman, Suzy

AU - Hanna, George B.

AU - Peters, Christopher J.

AU - Moorthy, Krishna

AU - Grabowska, Anna

AU - Turkington, Richard

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AU - Coleman, Helen

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N2 - 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.

AB - 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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JO - Nature Communications

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ER -

Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma

Abstract

ASJC Scopus subject areas

UN SDGs

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