Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis

the OCCAMS Consortium; 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 Tavaré; 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

doi:10.1038/ng.3013

Ordering of mutations in preinvasive disease stages of esophageal carcinogenesis

the OCCAMS Consortium, 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 HardwickJim Davies, Arusha Oloumi, Sam Aparicio, Carlos Caldas, Matthew D. Eldridge, Paul A.W. Edwards, Nitzan Rosenfeld, Simon Tavaré, 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

^*Corresponding author for this work

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

274 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
Early online date	22 Jun 2014
DOIs	https://doi.org/10.1038/ng.3013
Publication status	Published - Aug 2014

UN SDGs

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

Access to Document

10.1038/ng.3013

Andy Lynch
- andy.lynchst-andrews.acuk
- School of Medicine - Professor of Statistics in Bioscience
- School of Mathematics and Statistics - Professor
- Sir James Mackenzie Institute for Early Diagnosis
- St Andrews Bioinformatics Unit
- Cellular Medicine Division
Person: Academic

Cite this

the OCCAMS Consortium, Weaver, J. M. J., Ross-Innes, C. S., Shannon, N., Lynch, A. G., Forshew, T., Barbera, M., Murtaza, M., Ong, C. A. 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., ... Shepherd, N. (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{0ca76da471ae4b448c627c451917fb72,

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 = "{the OCCAMS Consortium} and 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{\'e} and Fitzgerald, {Rebecca C.} and Hayes, {Stephen J.} and Ang Yeng and Lydon, {Anne Marie} 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",

year = "2014",

month = aug,

doi = "10.1038/ng.3013",

language = "English",

volume = "46",

pages = "837--843",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature publishing group",

number = "8",

}

the OCCAMS Consortium, Weaver, JMJ, Ross-Innes, CS, Shannon, N, Lynch, AG, Forshew, T, Barbera, M, Murtaza, M, Ong, CAJ, 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, Tavaré, S, Fitzgerald, RC, Hayes, SJ, Yeng, A, Lydon, AM, 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 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 - the OCCAMS Consortium

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 - Tavaré, 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

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

AN - SCOPUS:84905502758

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

UN SDGs

Access to Document

Fingerprint

Profiles

Andy Lynch

Cite this