Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance

Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing owing to a lack of robust stratification methods. Whole-genome sequencing (WGS) analysis of 129 cases demonstrated that this is a heterogeneous cancer dominated by copy number alterations...

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Main Authors:	Secrier, Maria, Li, Xiaodun, de Silva, Nadeera, Eldridge, Matthew D., Contino, Gianmarco, Bornschein, Jan, MacRae, Shona, Grehan, Nicola, O'Donovan, Maria, Miremadi, Ahmad, Yang, Tsun-Po, Bower, Lawrence, Chettouh, Hamza, Crawte, Jason, Galeano-Dalmau, Núria, Grabowska, Anna, Saunders, John, Underwood, Tim, Waddell, Nicola, Barbour, Andrew P., Nutzinger, Barbara, Achilleos, Achilleas, Edwards, Paul A.W., Lynch, Andy G., Tavaré, Simon, Fitzgerald, Rebecca C., Noorani, Ayesha, Elliott, Rachael Fels, Weaver, Jamie, Ross-Innes, Caryn, Smith, Laura, Abdullahi, Zarah, de la Rue, Rachel, Cluroe, Alison, Malhotra, Shalini, Hardwick, Richard, Ford, Hugo, Smith, Mike L., Davies, Jim, Turkington, Richard, Hayes, Stephen J., Ang, Yeng, Preston, Shaun R., Oakes, Sarah, Bagwan, Izhar, Save, Vicki, Skipworth, Richard J.E., Hupp, Ted R., O'Neill, J. Robert, Tucker, Olga, Taniere, Philippe, Noble, Fergus, Owsley, Jack, Lovat, Laurence, Haidry, Rehan, Eneh, Victor, Crichton, Charles, Barr, Hugh, Shepherd, Neil, Old, Oliver, Lagergren, Jesper, Gossage, James, Davies, Andrew, Chang, Fuju, Zylstra, Janine, Sanders, Grant, Berrisford, Richard, Harden, Catherine, Bunting, David, Lewis, Mike, Cheong, Ed, Kumar, Bhaskar, Parsons, Simon L., Soomro, Irshad, Kaye, Philip, Collier, Pamela, Igali, Laszlo, Welch, Ian, Scott, Michael, Sothi, Shamila, Suortamo, Sari, Lishman, Suzy, Beardsmore, Duncan, Francies, Hayley E., Garnett, Mathew J., Pearson, John V., Nones, Katia, Patch, Ann-Marie, Grimmond, Sean M.
Format:	Article
Published:	Nature Publishing Group 2016
Subjects:	DNA sequencing Genetics research Oesophageal cancer
Online Access:	https://eprints.nottingham.ac.uk/40488/

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author	Secrier, Maria Li, Xiaodun de Silva, Nadeera Eldridge, Matthew D. Contino, Gianmarco Bornschein, Jan MacRae, Shona Grehan, Nicola O'Donovan, Maria Miremadi, Ahmad Yang, Tsun-Po Bower, Lawrence Chettouh, Hamza Crawte, Jason Galeano-Dalmau, Núria Grabowska, Anna Saunders, John Underwood, Tim Waddell, Nicola Barbour, Andrew P. Nutzinger, Barbara Achilleos, Achilleas Edwards, Paul A.W. Lynch, Andy G. Tavaré, Simon Fitzgerald, Rebecca C. Noorani, Ayesha Elliott, Rachael Fels Weaver, Jamie Ross-Innes, Caryn Smith, Laura Abdullahi, Zarah de la Rue, Rachel Cluroe, Alison Malhotra, Shalini Hardwick, Richard Ford, Hugo Smith, Mike L. Davies, Jim Turkington, Richard Hayes, Stephen J. Ang, Yeng Preston, Shaun R. Oakes, Sarah Bagwan, Izhar Save, Vicki Skipworth, Richard J.E. Hupp, Ted R. O'Neill, J. Robert Tucker, Olga Taniere, Philippe Noble, Fergus Owsley, Jack Lovat, Laurence Haidry, Rehan Eneh, Victor Crichton, Charles Barr, Hugh Shepherd, Neil Old, Oliver Lagergren, Jesper Gossage, James Davies, Andrew Chang, Fuju Zylstra, Janine Sanders, Grant Berrisford, Richard Harden, Catherine Bunting, David Lewis, Mike Cheong, Ed Kumar, Bhaskar Parsons, Simon L. Soomro, Irshad Kaye, Philip Collier, Pamela Igali, Laszlo Welch, Ian Scott, Michael Sothi, Shamila Suortamo, Sari Lishman, Suzy Beardsmore, Duncan Francies, Hayley E. Garnett, Mathew J. Pearson, John V. Nones, Katia Patch, Ann-Marie Grimmond, Sean M.
author_facet	Secrier, Maria Li, Xiaodun de Silva, Nadeera Eldridge, Matthew D. Contino, Gianmarco Bornschein, Jan MacRae, Shona Grehan, Nicola O'Donovan, Maria Miremadi, Ahmad Yang, Tsun-Po Bower, Lawrence Chettouh, Hamza Crawte, Jason Galeano-Dalmau, Núria Grabowska, Anna Saunders, John Underwood, Tim Waddell, Nicola Barbour, Andrew P. Nutzinger, Barbara Achilleos, Achilleas Edwards, Paul A.W. Lynch, Andy G. Tavaré, Simon Fitzgerald, Rebecca C. Noorani, Ayesha Elliott, Rachael Fels Weaver, Jamie Ross-Innes, Caryn Smith, Laura Abdullahi, Zarah de la Rue, Rachel Cluroe, Alison Malhotra, Shalini Hardwick, Richard Ford, Hugo Smith, Mike L. Davies, Jim Turkington, Richard Hayes, Stephen J. Ang, Yeng Preston, Shaun R. Oakes, Sarah Bagwan, Izhar Save, Vicki Skipworth, Richard J.E. Hupp, Ted R. O'Neill, J. Robert Tucker, Olga Taniere, Philippe Noble, Fergus Owsley, Jack Lovat, Laurence Haidry, Rehan Eneh, Victor Crichton, Charles Barr, Hugh Shepherd, Neil Old, Oliver Lagergren, Jesper Gossage, James Davies, Andrew Chang, Fuju Zylstra, Janine Sanders, Grant Berrisford, Richard Harden, Catherine Bunting, David Lewis, Mike Cheong, Ed Kumar, Bhaskar Parsons, Simon L. Soomro, Irshad Kaye, Philip Collier, Pamela Igali, Laszlo Welch, Ian Scott, Michael Sothi, Shamila Suortamo, Sari Lishman, Suzy Beardsmore, Duncan Francies, Hayley E. Garnett, Mathew J. Pearson, John V. Nones, Katia Patch, Ann-Marie Grimmond, Sean M.
author_sort	Secrier, Maria
building	Nottingham Research Data Repository
collection	Online Access
description	Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing owing to a lack of robust stratification methods. Whole-genome sequencing (WGS) analysis of 129 cases demonstrated that this is a heterogeneous cancer dominated by copy number alterations with frequent large-scale rearrangements. Co-amplification of receptor tyrosine kinases (RTKs) and/or downstream mitogenic activation is almost ubiquitous; thus tailored combination RTK inhibitor (RTKi) therapy might be required, as we demonstrate in vitro. However, mutational signatures showed three distinct molecular subtypes with potential therapeutic relevance, which we verified in an independent cohort (n = 87): (i) enrichment for BRCA signature with prevalent defects in the homologous recombination pathway; (ii) dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; and (iii) C>A/T mutational pattern with evidence of an aging imprint. These subtypes could be ascertained using a clinically applicable sequencing strategy (low coverage) as a basis for therapy selection.
first_indexed	2025-11-14T19:42:08Z
format	Article
id	nottingham-40488
institution	University of Nottingham Malaysia Campus
institution_category	Local University
last_indexed	2025-11-14T19:42:08Z
publishDate	2016
publisher	Nature Publishing Group
recordtype	eprints
repository_type	Digital Repository
spelling	nottingham-404882020-05-04T18:14:46Z https://eprints.nottingham.ac.uk/40488/ Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance Secrier, Maria Li, Xiaodun de Silva, Nadeera Eldridge, Matthew D. Contino, Gianmarco Bornschein, Jan MacRae, Shona Grehan, Nicola O'Donovan, Maria Miremadi, Ahmad Yang, Tsun-Po Bower, Lawrence Chettouh, Hamza Crawte, Jason Galeano-Dalmau, Núria Grabowska, Anna Saunders, John Underwood, Tim Waddell, Nicola Barbour, Andrew P. Nutzinger, Barbara Achilleos, Achilleas Edwards, Paul A.W. Lynch, Andy G. Tavaré, Simon Fitzgerald, Rebecca C. Noorani, Ayesha Elliott, Rachael Fels Weaver, Jamie Ross-Innes, Caryn Smith, Laura Abdullahi, Zarah de la Rue, Rachel Cluroe, Alison Malhotra, Shalini Hardwick, Richard Ford, Hugo Smith, Mike L. Davies, Jim Turkington, Richard Hayes, Stephen J. Ang, Yeng Preston, Shaun R. Oakes, Sarah Bagwan, Izhar Save, Vicki Skipworth, Richard J.E. Hupp, Ted R. O'Neill, J. Robert Tucker, Olga Taniere, Philippe Noble, Fergus Owsley, Jack Lovat, Laurence Haidry, Rehan Eneh, Victor Crichton, Charles Barr, Hugh Shepherd, Neil Old, Oliver Lagergren, Jesper Gossage, James Davies, Andrew Chang, Fuju Zylstra, Janine Sanders, Grant Berrisford, Richard Harden, Catherine Bunting, David Lewis, Mike Cheong, Ed Kumar, Bhaskar Parsons, Simon L. Soomro, Irshad Kaye, Philip Collier, Pamela Igali, Laszlo Welch, Ian Scott, Michael Sothi, Shamila Suortamo, Sari Lishman, Suzy Beardsmore, Duncan Francies, Hayley E. Garnett, Mathew J. Pearson, John V. Nones, Katia Patch, Ann-Marie Grimmond, Sean M. Esophageal adenocarcinoma (EAC) has a poor outcome, and targeted therapy trials have thus far been disappointing owing to a lack of robust stratification methods. Whole-genome sequencing (WGS) analysis of 129 cases demonstrated that this is a heterogeneous cancer dominated by copy number alterations with frequent large-scale rearrangements. Co-amplification of receptor tyrosine kinases (RTKs) and/or downstream mitogenic activation is almost ubiquitous; thus tailored combination RTK inhibitor (RTKi) therapy might be required, as we demonstrate in vitro. However, mutational signatures showed three distinct molecular subtypes with potential therapeutic relevance, which we verified in an independent cohort (n = 87): (i) enrichment for BRCA signature with prevalent defects in the homologous recombination pathway; (ii) dominant T>G mutational pattern associated with a high mutational load and neoantigen burden; and (iii) C>A/T mutational pattern with evidence of an aging imprint. These subtypes could be ascertained using a clinically applicable sequencing strategy (low coverage) as a basis for therapy selection. Nature Publishing Group 2016-10-31 Article PeerReviewed Secrier, Maria, Li, Xiaodun, de Silva, Nadeera, Eldridge, Matthew D., Contino, Gianmarco, Bornschein, Jan, MacRae, Shona, Grehan, Nicola, O'Donovan, Maria, Miremadi, Ahmad, Yang, Tsun-Po, Bower, Lawrence, Chettouh, Hamza, Crawte, Jason, Galeano-Dalmau, Núria, Grabowska, Anna, Saunders, John, Underwood, Tim, Waddell, Nicola, Barbour, Andrew P., Nutzinger, Barbara, Achilleos, Achilleas, Edwards, Paul A.W., Lynch, Andy G., Tavaré, Simon, Fitzgerald, Rebecca C., Noorani, Ayesha, Elliott, Rachael Fels, Weaver, Jamie, Ross-Innes, Caryn, Smith, Laura, Abdullahi, Zarah, de la Rue, Rachel, Cluroe, Alison, Malhotra, Shalini, Hardwick, Richard, Ford, Hugo, Smith, Mike L., Davies, Jim, Turkington, Richard, Hayes, Stephen J., Ang, Yeng, Preston, Shaun R., Oakes, Sarah, Bagwan, Izhar, Save, Vicki, Skipworth, Richard J.E., Hupp, Ted R., O'Neill, J. Robert, Tucker, Olga, Taniere, Philippe, Noble, Fergus, Owsley, Jack, Lovat, Laurence, Haidry, Rehan, Eneh, Victor, Crichton, Charles, Barr, Hugh, Shepherd, Neil, Old, Oliver, Lagergren, Jesper, Gossage, James, Davies, Andrew, Chang, Fuju, Zylstra, Janine, Sanders, Grant, Berrisford, Richard, Harden, Catherine, Bunting, David, Lewis, Mike, Cheong, Ed, Kumar, Bhaskar, Parsons, Simon L., Soomro, Irshad, Kaye, Philip, Collier, Pamela, Igali, Laszlo, Welch, Ian, Scott, Michael, Sothi, Shamila, Suortamo, Sari, Lishman, Suzy, Beardsmore, Duncan, Francies, Hayley E., Garnett, Mathew J., Pearson, John V., Nones, Katia, Patch, Ann-Marie and Grimmond, Sean M. (2016) Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance. Nature Genetics, 48 (10). pp. 1131-1141. ISSN 1546-1718 DNA sequencing Genetics research Oesophageal cancer http://dx.doi.org/10.1038/ng.3659 doi:10.1038/ng.3659 doi:10.1038/ng.3659
spellingShingle	DNA sequencing Genetics research Oesophageal cancer Secrier, Maria Li, Xiaodun de Silva, Nadeera Eldridge, Matthew D. Contino, Gianmarco Bornschein, Jan MacRae, Shona Grehan, Nicola O'Donovan, Maria Miremadi, Ahmad Yang, Tsun-Po Bower, Lawrence Chettouh, Hamza Crawte, Jason Galeano-Dalmau, Núria Grabowska, Anna Saunders, John Underwood, Tim Waddell, Nicola Barbour, Andrew P. Nutzinger, Barbara Achilleos, Achilleas Edwards, Paul A.W. Lynch, Andy G. Tavaré, Simon Fitzgerald, Rebecca C. Noorani, Ayesha Elliott, Rachael Fels Weaver, Jamie Ross-Innes, Caryn Smith, Laura Abdullahi, Zarah de la Rue, Rachel Cluroe, Alison Malhotra, Shalini Hardwick, Richard Ford, Hugo Smith, Mike L. Davies, Jim Turkington, Richard Hayes, Stephen J. Ang, Yeng Preston, Shaun R. Oakes, Sarah Bagwan, Izhar Save, Vicki Skipworth, Richard J.E. Hupp, Ted R. O'Neill, J. Robert Tucker, Olga Taniere, Philippe Noble, Fergus Owsley, Jack Lovat, Laurence Haidry, Rehan Eneh, Victor Crichton, Charles Barr, Hugh Shepherd, Neil Old, Oliver Lagergren, Jesper Gossage, James Davies, Andrew Chang, Fuju Zylstra, Janine Sanders, Grant Berrisford, Richard Harden, Catherine Bunting, David Lewis, Mike Cheong, Ed Kumar, Bhaskar Parsons, Simon L. Soomro, Irshad Kaye, Philip Collier, Pamela Igali, Laszlo Welch, Ian Scott, Michael Sothi, Shamila Suortamo, Sari Lishman, Suzy Beardsmore, Duncan Francies, Hayley E. Garnett, Mathew J. Pearson, John V. Nones, Katia Patch, Ann-Marie Grimmond, Sean M. Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance
title	Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance
title_full	Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance
title_fullStr	Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance
title_full_unstemmed	Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance
title_short	Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance
title_sort	mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance
topic	DNA sequencing Genetics research Oesophageal cancer
url	https://eprints.nottingham.ac.uk/40488/ https://eprints.nottingham.ac.uk/40488/ https://eprints.nottingham.ac.uk/40488/

Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance

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