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, Leslie 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 (Corresponding Author), Ian P. M. Tomlinson (Corresponding Author)

Research output: Contribution to journalArticlepeer-review

73 Citations (Scopus)


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 languageEnglish
Pages (from-to)1661-1672
Number of pages12
JournalNature Ecology and Evolution
Issue number10
Early online date31 Aug 2018
Publication statusPublished - Oct 2018

Bibliographical note

Supplementary information is available for this paper at
Raw data are available via the European Genome-Phenome Archive ( 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 (‘Förderung 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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