The evolutionary landscape of colorectal tumorigenesis

Roland Arnold, Laura Chegwidden, Xiaowei Jiang, Claire Palles, Ian P M Tomlinson, S:CORT Consortium, Simon Bach

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)
105 Downloads (Pure)

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 and Evolution
Volume2
Issue number10
Early online date31 Aug 2018
DOIs
Publication statusPublished - Oct 2018

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