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, Ian P. M. Tomlinson

Research output: Contribution to journalArticlepeer-review

63 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


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