The evolutionary landscape of colorectal tumorigenesis

William Cross, Michal Kovac, Ville Mustonen, Daniel Temko, Hayley Davis, Ann-Marie Baker, Sujata Biswas, 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, S:CORT ConsortiumMarnix 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

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 languageEnglish
Pages (from-to)1661-1672
Number of pages12
JournalNature Ecology & Evolution
Volume2
Issue number10
DOIs
Publication statusPublished - 31 Aug 2018

Keywords

  • Adenoma/genetics
  • Carcinogenesis/genetics
  • Carcinoma/genetics
  • Colorectal Neoplasms/genetics
  • Evolution, Molecular
  • Humans
  • Models, Biological
  • Mutation

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