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; Paul A.W. 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 J.E. Skipworth; Ted R. Hupp; J. Robert O’Neill; Olga Tucker; Andrew Beggs; Philippe Taniere; Sonia Puig; Gianmarco Contino; Timothy J. Underwood; Robert C. Walker; Michael Scott; Richard Turkington; Damian McManus; Helen Coleman; OCCAMS Consortium

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, Paul A.W. Edwards, Elwira Fidziukiewicz, Aisling M. Redmond, Adam Freeman, Elizabeth C. Smyth, Maria O’Donovan, Ahmad Miremadi, Shalini Malhotra, Monika Tripathi, Hannah ColesConor 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 J.E. Skipworth, Ted R. Hupp, J. Robert O’Neill, Olga Tucker, Andrew Beggs, Philippe Taniere, Sonia Puig, Gianmarco Contino, Timothy J. Underwood, Robert C. Walker, Michael Scott, Richard Turkington, Damian McManus, Helen Coleman, OCCAMS Consortium

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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
DOIs	https://doi.org/10.1038/s41467-023-39957-6
Publication status	Published - 15 Jul 2023

Bibliographical note

Funding Information:
The laboratory of R.C.F. was funded by a Core Programme Grant from the Medical Research Council (RG84369). OCCAMS2 was funded by a Programme Grant from Cancer Research UK (RG81771/84119, A22720/A22131). M.S. was supported by a UKRI Future Leaders Fellowship (MR/T042184/1). S.A. was funded by Cambridge Trust, Trinity College-Henry Barlow Trust and Basil Howard Research studentship from Sidney Sussex College Cambridge. N.L.-B. acknowledges funding from the European Research Council (consolidator grant 682398). IRB Barcelona is a recipient of a Severo Ochoa Centre of Excellence Award from Spanish Ministry of Science, Innovation and Universities (MICINN, Government of Spain) and is supported by CERCA (Generalitat de Catalunya). S.A.Z. is funded by the Gates Cambridge Trust, United Kingdom, and the Jack Kent Cooke Foundation, United States. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

Funding Information:
The laboratory of R.C.F. was funded by a Core Programme Grant from the Medical Research Council (RG84369). OCCAMS2 was funded by a Programme Grant from Cancer Research UK (RG81771/84119, A22720/A22131). M.S. was supported by a UKRI Future Leaders Fellowship (MR/T042184/1). S.A. was funded by Cambridge Trust, Trinity College-Henry Barlow Trust and Basil Howard Research studentship from Sidney Sussex College Cambridge. N.L.-B. acknowledges funding from the European Research Council (consolidator grant 682398). IRB Barcelona is a recipient of a Severo Ochoa Centre of Excellence Award from Spanish Ministry of Science, Innovation and Universities (MICINN, Government of Spain) and is supported by CERCA (Generalitat de Catalunya). S.A.Z. is funded by the Gates Cambridge Trust, United Kingdom, and the Jack Kent Cooke Foundation, United States. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

Publisher Copyright:
© 2023, The Author(s).

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

Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma
© 2023 The Authors. This is an open access article published under a Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Final published version, 5.13 MBLicence: CC BY

Cite this

Abbas, S., Pich, O., Devonshire, G., Zamani, S. A., Katz-Summercorn, A., Killcoyne, S., Cheah, C., Nutzinger, B., Grehan, N., Lopez-Bigas, N., Edwards, P. A. W., Fidziukiewicz, E., Redmond, A. M., Freeman, A., Smyth, E. C., O’Donovan, M., Miremadi, A., Malhotra, S., Tripathi, M., ... OCCAMS Consortium (2023). Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma. Nature Communications, 14(1), Article 4239. 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 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 Michael Scott and Richard Turkington and Damian McManus and Helen Coleman and {OCCAMS Consortium}",

note = "Funding Information: The laboratory of R.C.F. was funded by a Core Programme Grant from the Medical Research Council (RG84369). OCCAMS2 was funded by a Programme Grant from Cancer Research UK (RG81771/84119, A22720/A22131). M.S. was supported by a UKRI Future Leaders Fellowship (MR/T042184/1). S.A. was funded by Cambridge Trust, Trinity College-Henry Barlow Trust and Basil Howard Research studentship from Sidney Sussex College Cambridge. N.L.-B. acknowledges funding from the European Research Council (consolidator grant 682398). IRB Barcelona is a recipient of a Severo Ochoa Centre of Excellence Award from Spanish Ministry of Science, Innovation and Universities (MICINN, Government of Spain) and is supported by CERCA (Generalitat de Catalunya). S.A.Z. is funded by the Gates Cambridge Trust, United Kingdom, and the Jack Kent Cooke Foundation, United States. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. Funding Information: The laboratory of R.C.F. was funded by a Core Programme Grant from the Medical Research Council (RG84369). OCCAMS2 was funded by a Programme Grant from Cancer Research UK (RG81771/84119, A22720/A22131). M.S. was supported by a UKRI Future Leaders Fellowship (MR/T042184/1). S.A. was funded by Cambridge Trust, Trinity College-Henry Barlow Trust and Basil Howard Research studentship from Sidney Sussex College Cambridge. N.L.-B. acknowledges funding from the European Research Council (consolidator grant 682398). IRB Barcelona is a recipient of a Severo Ochoa Centre of Excellence Award from Spanish Ministry of Science, Innovation and Universities (MICINN, Government of Spain) and is supported by CERCA (Generalitat de Catalunya). S.A.Z. is funded by the Gates Cambridge Trust, United Kingdom, and the Jack Kent Cooke Foundation, United States. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

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Abbas, S, Pich, O, Devonshire, G, Zamani, SA, Katz-Summercorn, A, Killcoyne, S, Cheah, C, Nutzinger, B, Grehan, N, Lopez-Bigas, N, Edwards, PAW, Fidziukiewicz, E, Redmond, AM, Freeman, A, Smyth, EC, O’Donovan, M, Miremadi, A, Malhotra, S, Tripathi, M, Coles, H, Flint, C, Eldridge, M, Jammula, S, Davies, J, Crichton, C, Carroll, N, Hardwick, RH, Safranek, P, Hindmarsh, A, Sujendran, V, Hayes, SJ, Ang, Y, Sharrocks, A, Preston, SR, Bagwan, I, Save, V, Skipworth, RJE, Hupp, TR, O’Neill, JR, Tucker, O, Beggs, A, Taniere, P, Puig, S, Contino, G, Underwood, TJ, Walker, RC, Scott, M, Turkington, R, McManus, D, Coleman, H & OCCAMS Consortium 2023, 'Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma', Nature Communications, vol. 14, no. 1, 4239. https://doi.org/10.1038/s41467-023-39957-6

TY - JOUR

T1 - Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma

AU - Abbas, Sujath

AU - Pich, Oriol

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

AU - Edwards, Paul A.W.

AU - Fidziukiewicz, Elwira

AU - Redmond, Aisling M.

AU - Freeman, Adam

AU - Smyth, Elizabeth C.

AU - O’Donovan, Maria

AU - Miremadi, Ahmad

AU - Malhotra, Shalini

AU - Tripathi, Monika

AU - Coles, Hannah

AU - Flint, Conor

AU - Eldridge, Matthew

AU - Jammula, Sriganesh

AU - Davies, Jim

AU - Crichton, Charles

AU - Carroll, Nick

AU - Hardwick, Richard H.

AU - Safranek, Peter

AU - Hindmarsh, Andrew

AU - Sujendran, Vijayendran

AU - Hayes, Stephen J.

AU - Ang, Yeng

AU - Sharrocks, Andrew

AU - Preston, Shaun R.

AU - Bagwan, Izhar

AU - Save, Vicki

AU - Skipworth, Richard J.E.

AU - Hupp, Ted R.

AU - O’Neill, J. Robert

AU - Tucker, Olga

AU - Beggs, Andrew

AU - Taniere, Philippe

AU - Puig, Sonia

AU - Contino, Gianmarco

AU - Underwood, Timothy J.

AU - Walker, Robert C.

AU - Scott, Michael

AU - Turkington, Richard

AU - McManus, Damian

AU - Coleman, Helen

AU - OCCAMS Consortium

N1 - Funding Information: The laboratory of R.C.F. was funded by a Core Programme Grant from the Medical Research Council (RG84369). OCCAMS2 was funded by a Programme Grant from Cancer Research UK (RG81771/84119, A22720/A22131). M.S. was supported by a UKRI Future Leaders Fellowship (MR/T042184/1). S.A. was funded by Cambridge Trust, Trinity College-Henry Barlow Trust and Basil Howard Research studentship from Sidney Sussex College Cambridge. N.L.-B. acknowledges funding from the European Research Council (consolidator grant 682398). IRB Barcelona is a recipient of a Severo Ochoa Centre of Excellence Award from Spanish Ministry of Science, Innovation and Universities (MICINN, Government of Spain) and is supported by CERCA (Generalitat de Catalunya). S.A.Z. is funded by the Gates Cambridge Trust, United Kingdom, and the Jack Kent Cooke Foundation, United States. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. Funding Information: The laboratory of R.C.F. was funded by a Core Programme Grant from the Medical Research Council (RG84369). OCCAMS2 was funded by a Programme Grant from Cancer Research UK (RG81771/84119, A22720/A22131). M.S. was supported by a UKRI Future Leaders Fellowship (MR/T042184/1). S.A. was funded by Cambridge Trust, Trinity College-Henry Barlow Trust and Basil Howard Research studentship from Sidney Sussex College Cambridge. N.L.-B. acknowledges funding from the European Research Council (consolidator grant 682398). IRB Barcelona is a recipient of a Severo Ochoa Centre of Excellence Award from Spanish Ministry of Science, Innovation and Universities (MICINN, Government of Spain) and is supported by CERCA (Generalitat de Catalunya). S.A.Z. is funded by the Gates Cambridge Trust, United Kingdom, and the Jack Kent Cooke Foundation, United States. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. Publisher Copyright: © 2023, The Author(s).

PY - 2023/7/15

Y1 - 2023/7/15

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.

U2 - 10.1038/s41467-023-39957-6

DO - 10.1038/s41467-023-39957-6

M3 - Article

C2 - 37454136

AN - SCOPUS:85164754562

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4239

ER -

Mutational signature dynamics shaping the evolution of oesophageal adenocarcinoma

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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