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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 publication

DOI

10.1038/s41559-018-0642-z

Type

Journal article

Journal

Nat ecol evol

Publication Date

10/2018

Volume

2

Pages

1661 - 1672

Keywords

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