The evolutionary landscape of colorectal tumorigenesis

William Cross; Michal Kovac; Ville Mustonen; Daniel Temko; Hayley Davis; Sujata Biswas; Ann Marie Baker; Roland Arnold; Laura Chegwidden; Chandler Gatenbee; Alexander R. Anderson; Viktor H. Koelzer; Pierre Martinez; Xiaowei Jiang; Enric Domingo; Dan J. Woodcock; Yun Feng; Monika Kovacova; Tim Maughan; The S:CORT Consortium; Richard Adams; Simon Bach; Andrew Beggs; Louise Brown; Francesca Buffa; Jean Baptiste Cazier; Enric Domingo; Andrew Blake; Che Hsi Wu; Ekaterina Chatzpili; Susan Richman; Philip Dunne; Paul Harkin; Geoff Higgins; Jim Hill; Chris Holmes; Denis Horgan; Rick Kaplan; Richard Kennedy; Mark Lawler; Simon Leedham; Tim Maughan; Ultan McDermott; Gillies McKenna; Gary Middleton; Dion Morton; Graeme Murray; Phil Quirke; Manuel Salto-Tellez; Les Samuel; Anna Schuh; Marnix  Jansen; Manuel  Rodriguez-Justo; Shazad Ashraf; Richard  Guy; Christopher  Cunningham; James E.  East; David C.  Wedge; Lai Mun  Wang; Claire Palles; Karl  Heinimann; Andrea Sottoriva; Simon J.  Leedham; Trevor A.  Graham; Ian P. M. Tomlinson

doi:10.1038/s41559-018-0642-z

The evolutionary landscape of colorectal tumorigenesis

William Cross, Michal Kovac, Ville Mustonen, Daniel Temko, Hayley Davis, Sujata Biswas, Ann Marie Baker, Roland Arnold, Laura Chegwidden, Chandler Gatenbee, Alexander R. Anderson, Viktor H. Koelzer, Pierre Martinez, Xiaowei Jiang, Enric Domingo, Dan J. Woodcock, Yun Feng, Monika Kovacova, Tim Maughan, The S:CORT ConsortiumRichard Adams, Simon Bach, Andrew Beggs, Louise Brown, Francesca Buffa, Jean Baptiste Cazier, Enric Domingo, Andrew Blake, Che Hsi Wu, Ekaterina Chatzpili, Susan Richman, Philip Dunne, Paul Harkin, Geoff Higgins, Jim Hill, Chris Holmes, Denis Horgan, Rick Kaplan, Richard Kennedy, Mark Lawler, Simon Leedham, Tim Maughan, Ultan McDermott, Gillies McKenna, Gary Middleton, Dion Morton, Graeme Murray, Phil Quirke, Manuel Salto-Tellez, Les Samuel, Anna Schuh, Marnix Jansen, Manuel Rodriguez-Justo, Shazad Ashraf, Richard Guy, Christopher Cunningham, James E. East, David C. Wedge, Lai Mun Wang, Claire Palles, Karl Heinimann, Andrea Sottoriva, Simon J. Leedham, Trevor A. Graham, Ian P. M. Tomlinson

Medical Sciences

Research output: Contribution to journal › Article

17 Citations (Scopus)

Abstract

The evolutionary events that cause colorectal adenomas (benign) to progress to carcinomas (malignant) remain largely undetermined. Using multi-region genome and exome sequencing of 24 benign and malignant colorectal tumours, we investigate the evolutionary fitness landscape occupied by these neoplasms. Unlike carcinomas, advanced adenomas frequently harbour sub-clonal driver mutations—considered to be functionally important in the carcinogenic process—that have not swept to fixation, and have relatively high genetic heterogeneity. Carcinomas are distinguished from adenomas by widespread aneusomies that are usually clonal and often accrue in a ‘punctuated’ fashion. We conclude that adenomas evolve across an undulating fitness landscape, whereas carcinomas occupy a sharper fitness peak, probably owing to stabilizing selection.

Original language	English
Pages (from-to)	1661-1672
Number of pages	12
Journal	Nature Ecology and Evolution
Volume	2
Issue number	10
DOIs	https://doi.org/10.1038/s41559-018-0642-z
Publication status	Published - 31 Aug 2018

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ASJC Scopus subject areas

Ecology, Evolution, Behavior and Systematics
Ecology

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Cross, W., Kovac, M., Mustonen, V., Temko, D., Davis, H., Biswas, S., ... Tomlinson, I. P. M. (2018). The evolutionary landscape of colorectal tumorigenesis. Nature Ecology and Evolution, 2(10), 1661-1672. https://doi.org/10.1038/s41559-018-0642-z

The evolutionary landscape of colorectal tumorigenesis. / Cross, William; Kovac, Michal; Mustonen, Ville; Temko, Daniel; Davis, Hayley; Biswas, Sujata; Baker, Ann Marie; Arnold, Roland; Chegwidden, Laura; Gatenbee, Chandler; Anderson, Alexander R.; Koelzer, Viktor H.; Martinez, Pierre; Jiang, Xiaowei; Domingo, Enric; Woodcock, Dan J.; Feng, Yun; Kovacova, Monika; Maughan, Tim; The S:CORT Consortium; Adams, Richard; Bach, Simon; Beggs, Andrew; Brown, Louise; Buffa, Francesca; Cazier, Jean Baptiste; Domingo, Enric; Blake, Andrew; Wu, Che Hsi; Chatzpili, Ekaterina; Richman, Susan; Dunne, Philip; Harkin, Paul; Higgins, Geoff; Hill, Jim; Holmes, Chris; Horgan, Denis; Kaplan, Rick; Kennedy, Richard; Lawler, Mark; Leedham, Simon; Maughan, Tim; McDermott, Ultan; McKenna, Gillies; Middleton, Gary; Morton, Dion; Murray, Graeme; Quirke, Phil; Salto-Tellez, Manuel; Samuel, Les; Schuh, Anna; Jansen, Marnix ; Rodriguez-Justo, Manuel ; Ashraf, Shazad; Guy, Richard ; Cunningham, Christopher ; East, James E. ; Wedge, David C. ; Wang, Lai Mun ; Palles, Claire; Heinimann, Karl ; Sottoriva, Andrea; Leedham, Simon J. ; Graham, Trevor A. (Corresponding Author); Tomlinson, Ian P. M. (Corresponding Author).

In: Nature Ecology and Evolution, Vol. 2, No. 10, 31.08.2018, p. 1661-1672.

Research output: Contribution to journal › Article

Cross, W, Kovac, M, Mustonen, V, Temko, D, Davis, H, Biswas, S, Baker, AM, Arnold, R, Chegwidden, L, Gatenbee, C, Anderson, AR, Koelzer, VH, Martinez, P, Jiang, X, Domingo, E, Woodcock, DJ, Feng, Y, Kovacova, M, Maughan, T, The S:CORT Consortium, Adams, R, Bach, S, Beggs, A, Brown, L, Buffa, F, Cazier, JB, Domingo, E, Blake, A, Wu, CH, Chatzpili, E, Richman, S, Dunne, P, Harkin, P, Higgins, G, Hill, J, Holmes, C, Horgan, D, Kaplan, R, Kennedy, R, Lawler, M, Leedham, S, Maughan, T, McDermott, U, McKenna, G, Middleton, G, Morton, D, Murray, G, Quirke, P, Salto-Tellez, M, Samuel, L, Schuh, A, Jansen, M, Rodriguez-Justo, M, Ashraf, S, Guy, R, Cunningham, C, East, JE, Wedge, DC, Wang, LM, Palles, C, Heinimann, K, Sottoriva, A, Leedham, SJ, Graham, TA & Tomlinson, IPM 2018, 'The evolutionary landscape of colorectal tumorigenesis', Nature Ecology and Evolution, vol. 2, no. 10, pp. 1661-1672. https://doi.org/10.1038/s41559-018-0642-z

Cross, William ; Kovac, Michal ; Mustonen, Ville ; Temko, Daniel ; Davis, Hayley ; Biswas, Sujata ; Baker, Ann Marie ; Arnold, Roland ; Chegwidden, Laura ; Gatenbee, Chandler ; Anderson, Alexander R. ; Koelzer, Viktor H. ; Martinez, Pierre ; Jiang, Xiaowei ; Domingo, Enric ; Woodcock, Dan J. ; Feng, Yun ; Kovacova, Monika ; Maughan, Tim ; The S:CORT Consortium ; Adams, Richard ; Bach, Simon ; Beggs, Andrew ; Brown, Louise ; Buffa, Francesca ; Cazier, Jean Baptiste ; Domingo, Enric ; Blake, Andrew ; Wu, Che Hsi ; Chatzpili, Ekaterina ; Richman, Susan ; Dunne, Philip ; Harkin, Paul ; Higgins, Geoff ; Hill, Jim ; Holmes, Chris ; Horgan, Denis ; Kaplan, Rick ; Kennedy, Richard ; Lawler, Mark ; Leedham, Simon ; Maughan, Tim ; McDermott, Ultan ; McKenna, Gillies ; Middleton, Gary ; Morton, Dion ; Murray, Graeme ; Quirke, Phil ; Salto-Tellez, Manuel ; Samuel, Les ; Schuh, Anna ; Jansen, Marnix ; Rodriguez-Justo, Manuel ; Ashraf, Shazad ; Guy, Richard ; Cunningham, Christopher ; East, James E. ; Wedge, David C. ; Wang, Lai Mun ; Palles, Claire ; Heinimann, Karl ; Sottoriva, Andrea ; Leedham, Simon J. ; Graham, Trevor A. ; Tomlinson, Ian P. M. / The evolutionary landscape of colorectal tumorigenesis. In: Nature Ecology and Evolution. 2018 ; Vol. 2, No. 10. pp. 1661-1672.

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title = "The evolutionary landscape of colorectal tumorigenesis",

abstract = "The evolutionary events that cause colorectal adenomas (benign) to progress to carcinomas (malignant) remain largely undetermined. Using multi-region genome and exome sequencing of 24 benign and malignant colorectal tumours, we investigate the evolutionary fitness landscape occupied by these neoplasms. Unlike carcinomas, advanced adenomas frequently harbour sub-clonal driver mutations—considered to be functionally important in the carcinogenic process—that have not swept to fixation, and have relatively high genetic heterogeneity. Carcinomas are distinguished from adenomas by widespread aneusomies that are usually clonal and often accrue in a ‘punctuated’ fashion. We conclude that adenomas evolve across an undulating fitness landscape, whereas carcinomas occupy a sharper fitness peak, probably owing to stabilizing selection.",

author = "William Cross and Michal Kovac and Ville Mustonen and Daniel Temko and Hayley Davis and Sujata Biswas and Baker, {Ann Marie} and Roland Arnold and Laura Chegwidden and Chandler Gatenbee and Anderson, {Alexander R.} and Koelzer, {Viktor H.} and Pierre Martinez and Xiaowei Jiang and Enric Domingo and Woodcock, {Dan J.} and Yun Feng and Monika Kovacova and Tim Maughan and {The S:CORT Consortium} and Richard Adams and Simon Bach and Andrew Beggs and Louise Brown and Francesca Buffa and Cazier, {Jean Baptiste} and Enric Domingo and Andrew Blake and Wu, {Che Hsi} and Ekaterina Chatzpili and Susan Richman and Philip Dunne and Paul Harkin and Geoff Higgins and Jim Hill and Chris Holmes and Denis Horgan and Rick Kaplan and Richard Kennedy and Mark Lawler and Simon Leedham and Tim Maughan and Ultan McDermott and Gillies McKenna and Gary Middleton and Dion Morton and Graeme Murray and Phil Quirke and Manuel Salto-Tellez and Les Samuel and Anna Schuh and Marnix Jansen and Manuel Rodriguez-Justo and Shazad Ashraf and Richard Guy and Christopher Cunningham and East, {James E.} and Wedge, {David C.} and Wang, {Lai Mun} and Claire Palles and Karl Heinimann and Andrea Sottoriva and Leedham, {Simon J.} and Graham, {Trevor A.} and Tomlinson, {Ian P. M.}",

note = "Supplementary information is available for this paper at https://doi.org/10.1038/ s41559-018-0642-z Raw data are available via the European Genome-Phenome Archive (https://ega-archive.org/) accession code: EGAS00001003066. S.J.L., T.A.G. (A19771) and I.P.M.T. (A27327) are funded by Cancer Research UK. We acknowledge core funding provided to the Wellcome Trust Centre for Human Genetics from the Wellcome Trust (090532/Z/09/Z). T.A.G. and S.J.L. were also supported by the Bowel and Cancer Research small grant scheme. T.A.G. was also supported by the Wellcome Trust (202778/Z/16/Z). V.M. was supported in part by funding from the Wellcome Trust (098051). M. Kovac was supported by the Krebsligabeider Basel (grant no. KLBB-12-2013) and the University of Basel (‘F{\"o}rderung exzellenter Nachwuchsforschender’). A-M.B. also acknowledges funding from Cancer Research UK (A14895). D.C.W. is supported by the Li Ka Shing Foundation. X.J. and I.P.M.T. are supported by an ERC advanced grant (EVOCAN-340560). The S:CORT study is funded by the MRC and Cancer Research UK. K.H is supported by Krebsliga Zentralschweiz. A.S. is supported by the Wellcome Trust (202778/B/16/Z), Cancer Research UK (A22909) and the Chris Rokos Fellowship in Evolution and Cancer. This work was also supported a Wellcome Trust award to the Centre for Evolution and Cancer (105104/Z/14/Z). J.E.E. was funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). V.H.K. was funded by the Swiss National Science Foundation (P2SKP3_168322 / 1 and P2SKP3_168322 / 2). D.T. acknowledges funding from the EPSRC (grant no.: EP/F500351/1).",

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AU - Cross, William

AU - Kovac, Michal

AU - Mustonen, Ville

AU - Temko, Daniel

AU - Davis, Hayley

AU - Biswas, Sujata

AU - Baker, Ann Marie

AU - Arnold, Roland

AU - Chegwidden, Laura

AU - Gatenbee, Chandler

AU - Anderson, Alexander R.

AU - Koelzer, Viktor H.

AU - Martinez, Pierre

AU - Jiang, Xiaowei

AU - Domingo, Enric

AU - Woodcock, Dan J.

AU - Feng, Yun

AU - Kovacova, Monika

AU - Maughan, Tim

AU - The S:CORT Consortium

AU - Adams, Richard

AU - Bach, Simon

AU - Beggs, Andrew

AU - Brown, Louise

AU - Buffa, Francesca

AU - Cazier, Jean Baptiste

AU - Domingo, Enric

AU - Blake, Andrew

AU - Wu, Che Hsi

AU - Chatzpili, Ekaterina

AU - Richman, Susan

AU - Dunne, Philip

AU - Harkin, Paul

AU - Higgins, Geoff

AU - Hill, Jim

AU - Holmes, Chris

AU - Horgan, Denis

AU - Kaplan, Rick

AU - Kennedy, Richard

AU - Lawler, Mark

AU - Leedham, Simon

AU - Maughan, Tim

AU - McDermott, Ultan

AU - McKenna, Gillies

AU - Middleton, Gary

AU - Morton, Dion

AU - Murray, Graeme

AU - Quirke, Phil

AU - Salto-Tellez, Manuel

AU - Samuel, Les

AU - Schuh, Anna

AU - Jansen, Marnix

AU - Rodriguez-Justo, Manuel

AU - Ashraf, Shazad

AU - Guy, Richard

AU - Cunningham, Christopher

AU - East, James E.

AU - Wedge, David C.

AU - Wang, Lai Mun

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AU - Graham, Trevor A.

AU - Tomlinson, Ian P. M.

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N2 - The evolutionary events that cause colorectal adenomas (benign) to progress to carcinomas (malignant) remain largely undetermined. Using multi-region genome and exome sequencing of 24 benign and malignant colorectal tumours, we investigate the evolutionary fitness landscape occupied by these neoplasms. Unlike carcinomas, advanced adenomas frequently harbour sub-clonal driver mutations—considered to be functionally important in the carcinogenic process—that have not swept to fixation, and have relatively high genetic heterogeneity. Carcinomas are distinguished from adenomas by widespread aneusomies that are usually clonal and often accrue in a ‘punctuated’ fashion. We conclude that adenomas evolve across an undulating fitness landscape, whereas carcinomas occupy a sharper fitness peak, probably owing to stabilizing selection.

AB - The evolutionary events that cause colorectal adenomas (benign) to progress to carcinomas (malignant) remain largely undetermined. Using multi-region genome and exome sequencing of 24 benign and malignant colorectal tumours, we investigate the evolutionary fitness landscape occupied by these neoplasms. Unlike carcinomas, advanced adenomas frequently harbour sub-clonal driver mutations—considered to be functionally important in the carcinogenic process—that have not swept to fixation, and have relatively high genetic heterogeneity. Carcinomas are distinguished from adenomas by widespread aneusomies that are usually clonal and often accrue in a ‘punctuated’ fashion. We conclude that adenomas evolve across an undulating fitness landscape, whereas carcinomas occupy a sharper fitness peak, probably owing to stabilizing selection.

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