Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis

Jamie M J Weaver; Caryn S Ross-innes; Nicholas Shannon; Andy G Lynch; Tim Forshew; Mariagnese Barbera; Muhammed Murtaza; Chin-ann J Ong; Pierre Lao-sirieix; Mark J Dunning; Laura Smith; Mike L Smith; Charlotte L Anderson; Benilton Carvalho; Maria O'donovan; Timothy J Underwood; Andrew P May; Nicola Grehan; Richard Hardwick; Jim Davies; Arusha Oloumi; Sam Aparicio; Carlos Caldas; Matthew D Eldridge; Paul A W Edwards; Nitzan Rosenfeld; Simon Tavar??; Rebecca C Fitzgerald; Stephen J Hayes; Ang Yeng; Anne-marie Lydon; Soney Dharmaprasad; Sandra Greer; Shaun Preston; Sarah Oakes; Vicki Save; Simon Paterson-brown; Olga Tucker; Derek Alderson; Philippe Taniere; Jamie Kelly; James Byrne; Donna Sharland; Nina Holling; Lisa Boulter; Fergus Noble; Bernard Stacey; Charles Crichton; Hugh Barr; Neil Shepherd; L Max Almond; Oliver Old; Jesper Lagergren; James Gossage; Andrew Davies; Robert Mason; Fuju Chang; Janine Zylstra; Grant Sanders; Tim Wheatley; Richard Berrisford; Tim Bracey; Catherine Harden; David Bunting; Tom Roques; Jenny Nobes; Suat Loo; Mike Lewis; Ed Cheong; Oliver Priest; Simon L Parsons; Irshad Soomro; Philip Kaye; John Saunders; Vincent Pang; Neil T Welch; James A Catton; John P Duffy; Krish Ragunath; Laurence Lovat; Rehan Haidry; Haroon Miah; Sarah Kerr; Victor Eneh; Rommel Butawan; Laszlo Igali; Hugo Ford; David Gilligan; Peter Safranek; Andy Hindmarsh; Vijayendran Sudjendran; Andy Metz; Nick Carroll; Michael Scott; Alison Cluroe; Ahmad Miremadi; Betania Mahler-araujo; Olga Knight; Barbara Nutzinger; Chris Peters; Zarah Abdullahi; Irene Debriram-beecham; Shalini Malhotra; Jason Crawte; Shona Macrae; Ayesha Noorani; Rachael Fels Elliott; Xiaodun Li; Lawrence Bower; Achilleas Achilleos; Jan Bornschein; Sebastian Zeki; Hamza Chettouh; Maria Secrier; Nadeera De Silva; Eleanor Gregson; Tsun-po Yang; J Robert O'neil

doi:10.1038/ng.3013

Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis

Jamie M J Weaver, Caryn S Ross-innes, Nicholas Shannon, Andy G Lynch, Tim Forshew, Mariagnese Barbera, Muhammed Murtaza, Chin-ann J Ong, Pierre Lao-sirieix, Mark J Dunning, Laura Smith, Mike L Smith, Charlotte L Anderson, Benilton Carvalho, Maria O'donovan, Timothy J Underwood, Andrew P May, Nicola Grehan, Richard Hardwick, Jim DaviesArusha Oloumi, Sam Aparicio, Carlos Caldas, Matthew D Eldridge, Paul A W Edwards, Nitzan Rosenfeld, Simon Tavar??, Rebecca C Fitzgerald, Stephen J Hayes, Ang Yeng, Anne-marie Lydon, Soney Dharmaprasad, Sandra Greer, Shaun Preston, Sarah Oakes, Vicki Save, Simon Paterson-brown, Olga Tucker, Derek Alderson, Philippe Taniere, Jamie Kelly, James Byrne, Donna Sharland, Nina Holling, Lisa Boulter, Fergus Noble, Bernard Stacey, Charles Crichton, Hugh Barr, Neil Shepherd, L Max Almond, Oliver Old, Jesper Lagergren, James Gossage, Andrew Davies, Robert Mason, Fuju Chang, Janine Zylstra, Grant Sanders, Tim Wheatley, Richard Berrisford, Tim Bracey, Catherine Harden, David Bunting, Tom Roques, Jenny Nobes, Suat Loo, Mike Lewis, Ed Cheong, Oliver Priest, Simon L Parsons, Irshad Soomro, Philip Kaye, John Saunders, Vincent Pang, Neil T Welch, James A Catton, John P Duffy, Krish Ragunath, Laurence Lovat, Rehan Haidry, Haroon Miah, Sarah Kerr, Victor Eneh, Rommel Butawan, Laszlo Igali, Hugo Ford, David Gilligan, Peter Safranek, Andy Hindmarsh, Vijayendran Sudjendran, Andy Metz, Nick Carroll, Michael Scott, Alison Cluroe, Ahmad Miremadi, Betania Mahler-araujo, Olga Knight, Barbara Nutzinger, Chris Peters, Zarah Abdullahi, Irene Debriram-beecham, Shalini Malhotra, Jason Crawte, Shona Macrae, Ayesha Noorani, Rachael Fels Elliott, Xiaodun Li, Lawrence Bower, Achilleas Achilleos, Jan Bornschein, Sebastian Zeki, Hamza Chettouh, Maria Secrier, Nadeera De Silva, Eleanor Gregson, Tsun-po Yang, J Robert O'neil

King's College London

Research output: Contribution to journal › Article › peer-review

278 Citations (Scopus)

Abstract

Cancer genome sequencing studies have identified numerous driver genes, but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from premalignant Barrett's esophagus to esophageal adenocarcinoma (EAC) provides an ideal model to study the ordering of somatic mutations. We identified recurrently mutated genes and assessed clonal structure using whole-genome sequencing and amplicon resequencing of 112 EACs. We next screened a cohort of 109 biopsies from 2 key transition points in the development of malignancy: benign metaplastic never-dysplastic Barrett's esophagus (NDBE; n = 66) and high-grade dysplasia (HGD; n = 43). Unexpectedly, the majority of recurrently mutated genes in EAC were also mutated in NDBE. Only TP53 and SMAD4 mutations occurred in a stage-specific manner, confined to HGD and EAC, respectively. Finally, we applied this knowledge to identify high-risk Barrett's esophagus in a new non-endoscopic test. In conclusion, mutations in EAC driver genes generally occur exceptionally early in disease development with profound implications for diagnostic and therapeutic strategies.

Original language	English
Pages (from-to)	837-843
Number of pages	7
Journal	Nature Genetics
Volume	46
Issue number	8
DOIs	https://doi.org/10.1038/ng.3013
Publication status	Published - Aug 2014

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10.1038/ng.3013

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Weaver, J. M. J., Ross-innes, C. S., Shannon, N., Lynch, A. G., Forshew, T., Barbera, M., Murtaza, M., Ong, C. J., Lao-sirieix, P., Dunning, M. J., Smith, L., Smith, M. L., Anderson, C. L., Carvalho, B., O'donovan, M., Underwood, T. J., May, A. P., Grehan, N., Hardwick, R., ... O'neil, J. R. (2014). Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis. Nature Genetics, 46(8), 837-843. https://doi.org/10.1038/ng.3013

@article{85797a8e3a0e470e8d461ae8d033cb86,

title = "Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis",

abstract = "Cancer genome sequencing studies have identified numerous driver genes, but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from premalignant Barrett's esophagus to esophageal adenocarcinoma (EAC) provides an ideal model to study the ordering of somatic mutations. We identified recurrently mutated genes and assessed clonal structure using whole-genome sequencing and amplicon resequencing of 112 EACs. We next screened a cohort of 109 biopsies from 2 key transition points in the development of malignancy: benign metaplastic never-dysplastic Barrett's esophagus (NDBE; n = 66) and high-grade dysplasia (HGD; n = 43). Unexpectedly, the majority of recurrently mutated genes in EAC were also mutated in NDBE. Only TP53 and SMAD4 mutations occurred in a stage-specific manner, confined to HGD and EAC, respectively. Finally, we applied this knowledge to identify high-risk Barrett's esophagus in a new non-endoscopic test. In conclusion, mutations in EAC driver genes generally occur exceptionally early in disease development with profound implications for diagnostic and therapeutic strategies.",

author = "Weaver, {Jamie M J} and Ross-innes, {Caryn S} and Nicholas Shannon and Lynch, {Andy G} and Tim Forshew and Mariagnese Barbera and Muhammed Murtaza and Ong, {Chin-ann J} and Pierre Lao-sirieix and Dunning, {Mark J} and Laura Smith and Smith, {Mike L} and Anderson, {Charlotte L} and Benilton Carvalho and Maria O'donovan and Underwood, {Timothy J} and May, {Andrew P} and Nicola Grehan and Richard Hardwick and Jim Davies and Arusha Oloumi and Sam Aparicio and Carlos Caldas and Eldridge, {Matthew D} and Edwards, {Paul A W} and Nitzan Rosenfeld and Simon Tavar?? and Fitzgerald, {Rebecca C} and Hayes, {Stephen J} and Ang Yeng and Anne-marie Lydon and Soney Dharmaprasad and Sandra Greer and Shaun Preston and Sarah Oakes and Vicki Save and Simon Paterson-brown and Olga Tucker and Derek Alderson and Philippe Taniere and Jamie Kelly and James Byrne and Donna Sharland and Nina Holling and Lisa Boulter and Fergus Noble and Bernard Stacey and Charles Crichton and Hugh Barr and Neil Shepherd and Almond, {L Max} and Oliver Old and Jesper Lagergren and James Gossage and Andrew Davies and Robert Mason and Fuju Chang and Janine Zylstra and Grant Sanders and Tim Wheatley and Richard Berrisford and Tim Bracey and Catherine Harden and David Bunting and Tom Roques and Jenny Nobes and Suat Loo and Mike Lewis and Ed Cheong and Oliver Priest and Parsons, {Simon L} and Irshad Soomro and Philip Kaye and John Saunders and Vincent Pang and Welch, {Neil T} and Catton, {James A} and Duffy, {John P} and Krish Ragunath and Laurence Lovat and Rehan Haidry and Haroon Miah and Sarah Kerr and Victor Eneh and Rommel Butawan and Laszlo Igali and Hugo Ford and David Gilligan and Peter Safranek and Andy Hindmarsh and Vijayendran Sudjendran and Andy Metz and Nick Carroll and Michael Scott and Alison Cluroe and Ahmad Miremadi and Betania Mahler-araujo and Olga Knight and Barbara Nutzinger and Chris Peters and Zarah Abdullahi and Irene Debriram-beecham and Shalini Malhotra and Jason Crawte and Shona Macrae and Ayesha Noorani and Elliott, {Rachael Fels} and Xiaodun Li and Lawrence Bower and Achilleas Achilleos and Jan Bornschein and Sebastian Zeki and Hamza Chettouh and Maria Secrier and {De Silva}, Nadeera and Eleanor Gregson and Tsun-po Yang and O'neil, {J Robert}",

year = "2014",

month = aug,

doi = "10.1038/ng.3013",

language = "English",

volume = "46",

pages = "837--843",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "8",

}

Weaver, JMJ, Ross-innes, CS, Shannon, N, Lynch, AG, Forshew, T, Barbera, M, Murtaza, M, Ong, CJ, Lao-sirieix, P, Dunning, MJ, Smith, L, Smith, ML, Anderson, CL, Carvalho, B, O'donovan, M, Underwood, TJ, May, AP, Grehan, N, Hardwick, R, Davies, J, Oloumi, A, Aparicio, S, Caldas, C, Eldridge, MD, Edwards, PAW, Rosenfeld, N, Tavar??, S, Fitzgerald, RC, Hayes, SJ, Yeng, A, Lydon, A, Dharmaprasad, S, Greer, S, Preston, S, Oakes, S, Save, V, Paterson-brown, S, Tucker, O, Alderson, D, Taniere, P, Kelly, J, Byrne, J, Sharland, D, Holling, N, Boulter, L, Noble, F, Stacey, B, Crichton, C, Barr, H, Shepherd, N, Almond, LM, Old, O, Lagergren, J , Gossage, J , Davies, A , Mason, R , Chang, F , Zylstra, J, Sanders, G, Wheatley, T, Berrisford, R, Bracey, T, Harden, C, Bunting, D, Roques, T, Nobes, J, Loo, S, Lewis, M, Cheong, E, Priest, O, Parsons, SL, Soomro, I, Kaye, P, Saunders, J, Pang, V, Welch, NT, Catton, JA, Duffy, JP, Ragunath, K, Lovat, L, Haidry, R, Miah, H, Kerr, S, Eneh, V, Butawan, R, Igali, L, Ford, H, Gilligan, D, Safranek, P, Hindmarsh, A, Sudjendran, V, Metz, A, Carroll, N, Scott, M, Cluroe, A, Miremadi, A, Mahler-araujo, B, Knight, O, Nutzinger, B, Peters, C, Abdullahi, Z, Debriram-beecham, I, Malhotra, S, Crawte, J, Macrae, S, Noorani, A, Elliott, RF, Li, X, Bower, L, Achilleos, A, Bornschein, J, Zeki, S, Chettouh, H, Secrier, M, De Silva, N, Gregson, E, Yang, T & O'neil, JR 2014, 'Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis', Nature Genetics, vol. 46, no. 8, pp. 837-843. https://doi.org/10.1038/ng.3013

TY - JOUR

T1 - Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis

AU - Weaver, Jamie M J

AU - Ross-innes, Caryn S

AU - Shannon, Nicholas

AU - Lynch, Andy G

AU - Forshew, Tim

AU - Barbera, Mariagnese

AU - Murtaza, Muhammed

AU - Ong, Chin-ann J

AU - Lao-sirieix, Pierre

AU - Dunning, Mark J

AU - Smith, Laura

AU - Smith, Mike L

AU - Anderson, Charlotte L

AU - Carvalho, Benilton

AU - O'donovan, Maria

AU - Underwood, Timothy J

AU - May, Andrew P

AU - Grehan, Nicola

AU - Hardwick, Richard

AU - Davies, Jim

AU - Oloumi, Arusha

AU - Aparicio, Sam

AU - Caldas, Carlos

AU - Eldridge, Matthew D

AU - Edwards, Paul A W

AU - Rosenfeld, Nitzan

AU - Tavar??, Simon

AU - Fitzgerald, Rebecca C

AU - Hayes, Stephen J

AU - Yeng, Ang

AU - Lydon, Anne-marie

AU - Dharmaprasad, Soney

AU - Greer, Sandra

AU - Preston, Shaun

AU - Oakes, Sarah

AU - Save, Vicki

AU - Paterson-brown, Simon

AU - Tucker, Olga

AU - Alderson, Derek

AU - Taniere, Philippe

AU - Kelly, Jamie

AU - Byrne, James

AU - Sharland, Donna

AU - Holling, Nina

AU - Boulter, Lisa

AU - Noble, Fergus

AU - Stacey, Bernard

AU - Crichton, Charles

AU - Barr, Hugh

AU - Shepherd, Neil

AU - Almond, L Max

AU - Old, Oliver

AU - Lagergren, Jesper

AU - Gossage, James

AU - Davies, Andrew

AU - Mason, Robert

AU - Chang, Fuju

AU - Zylstra, Janine

AU - Sanders, Grant

AU - Wheatley, Tim

AU - Berrisford, Richard

AU - Bracey, Tim

AU - Harden, Catherine

AU - Bunting, David

AU - Roques, Tom

AU - Nobes, Jenny

AU - Loo, Suat

AU - Lewis, Mike

AU - Cheong, Ed

AU - Priest, Oliver

AU - Parsons, Simon L

AU - Soomro, Irshad

AU - Kaye, Philip

AU - Saunders, John

AU - Pang, Vincent

AU - Welch, Neil T

AU - Catton, James A

AU - Duffy, John P

AU - Ragunath, Krish

AU - Lovat, Laurence

AU - Haidry, Rehan

AU - Miah, Haroon

AU - Kerr, Sarah

AU - Eneh, Victor

AU - Butawan, Rommel

AU - Igali, Laszlo

AU - Ford, Hugo

AU - Gilligan, David

AU - Safranek, Peter

AU - Hindmarsh, Andy

AU - Sudjendran, Vijayendran

AU - Metz, Andy

AU - Carroll, Nick

AU - Scott, Michael

AU - Cluroe, Alison

AU - Miremadi, Ahmad

AU - Mahler-araujo, Betania

AU - Knight, Olga

AU - Nutzinger, Barbara

AU - Peters, Chris

AU - Abdullahi, Zarah

AU - Debriram-beecham, Irene

AU - Malhotra, Shalini

AU - Crawte, Jason

AU - Macrae, Shona

AU - Noorani, Ayesha

AU - Elliott, Rachael Fels

AU - Li, Xiaodun

AU - Bower, Lawrence

AU - Achilleos, Achilleas

AU - Bornschein, Jan

AU - Zeki, Sebastian

AU - Chettouh, Hamza

AU - Secrier, Maria

AU - De Silva, Nadeera

AU - Gregson, Eleanor

AU - Yang, Tsun-po

AU - O'neil, J Robert

PY - 2014/8

Y1 - 2014/8

N2 - Cancer genome sequencing studies have identified numerous driver genes, but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from premalignant Barrett's esophagus to esophageal adenocarcinoma (EAC) provides an ideal model to study the ordering of somatic mutations. We identified recurrently mutated genes and assessed clonal structure using whole-genome sequencing and amplicon resequencing of 112 EACs. We next screened a cohort of 109 biopsies from 2 key transition points in the development of malignancy: benign metaplastic never-dysplastic Barrett's esophagus (NDBE; n = 66) and high-grade dysplasia (HGD; n = 43). Unexpectedly, the majority of recurrently mutated genes in EAC were also mutated in NDBE. Only TP53 and SMAD4 mutations occurred in a stage-specific manner, confined to HGD and EAC, respectively. Finally, we applied this knowledge to identify high-risk Barrett's esophagus in a new non-endoscopic test. In conclusion, mutations in EAC driver genes generally occur exceptionally early in disease development with profound implications for diagnostic and therapeutic strategies.

AB - Cancer genome sequencing studies have identified numerous driver genes, but the relative timing of mutations in carcinogenesis remains unclear. The gradual progression from premalignant Barrett's esophagus to esophageal adenocarcinoma (EAC) provides an ideal model to study the ordering of somatic mutations. We identified recurrently mutated genes and assessed clonal structure using whole-genome sequencing and amplicon resequencing of 112 EACs. We next screened a cohort of 109 biopsies from 2 key transition points in the development of malignancy: benign metaplastic never-dysplastic Barrett's esophagus (NDBE; n = 66) and high-grade dysplasia (HGD; n = 43). Unexpectedly, the majority of recurrently mutated genes in EAC were also mutated in NDBE. Only TP53 and SMAD4 mutations occurred in a stage-specific manner, confined to HGD and EAC, respectively. Finally, we applied this knowledge to identify high-risk Barrett's esophagus in a new non-endoscopic test. In conclusion, mutations in EAC driver genes generally occur exceptionally early in disease development with profound implications for diagnostic and therapeutic strategies.

U2 - 10.1038/ng.3013

DO - 10.1038/ng.3013

M3 - Article

SN - 1061-4036

VL - 46

SP - 837

EP - 843

JO - Nature Genetics

JF - Nature Genetics

IS - 8

ER -

Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis

Abstract

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