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The evolutionary landscape of colorectal tumorigenesis.

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.

SUBMITTER: Cross W

PROVIDER: S-EPMC6152905 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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The evolutionary landscape of colorectal tumorigenesis.

Cross William W Kovac Michal M Mustonen Ville V Temko Daniel D Davis Hayley H Baker Ann-Marie AM Baker Ann-Marie AM Biswas Sujata S Arnold Roland R Chegwidden Laura L Gatenbee Chandler C Anderson Alexander R AR Koelzer Viktor H VH Martinez Pierre P Jiang Xiaowei X Domingo Enric E Woodcock Dan J DJ Feng Yun Y Kovacova Monika M Maughan Tim T Jansen Marnix M Rodriguez-Justo Manuel M Ashraf Shazad S Guy Richard R Cunningham Christopher C East James E JE Wedge David C DC Wang Lai Mun LM Palles Claire C Heinimann Karl K Sottoriva Andrea A Leedham Simon J SJ Graham Trevor A TA Tomlinson Ian P M IPM

Nature ecology & evolution 20180831 10

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 re ...[more]

PMID: 30177804

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Project description:From the perspective of systems science, tumorigenesis can be hypothesized as a critical transition (an abrupt shift from one state to another) between proliferative and apoptotic attractors on the state space of a molecular interaction network, for which an attractor is defined as a stable state to which all initial states ultimately converge, and the region of convergence is called the basin of attraction. Before the critical transition, a cellular state might transit between the basin of attraction for an apoptotic attractor and that for a proliferative attractor due to the noise induced by the inherent stochasticity in molecular interactions. Such a flickering state transition (state transition between the basins of attraction for alternative attractors from the impact of noise) would become more frequent as the cellular state approaches near the boundary of the basin of attraction, which can increase the variation in the estimate of the respective basin size. To investigate this for colorectal tumorigenesis, we have constructed a stochastic Boolean network model of the molecular interaction network that contains an important set of proteins known to be involved in cancer. In particular, we considered 100 representative sequences of 20 gene mutations that drive colorectal tumorigenesis. We investigated the appearance of cancerous cells by examining the basin size of apoptotic, quiescent, and proliferative attractors along with the sequential accumulation of gene mutations during colorectal tumorigenesis. We introduced a measure to detect the flickering state transition as the variation in the estimate of the basin sizes for three-phenotype attractors from the impact of noise. Interestingly, we found that this measure abruptly increases before a cell becomes cancerous during colorectal tumorigenesis in most of the gene mutation sequences under a certain level of stochastic noise. This suggests that a frequent flickering state transition can be a precritical phenomenon of colorectal tumorigenesis.

Dataset Information

The evolutionary landscape of colorectal tumorigenesis.

Publications

The evolutionary landscape of colorectal tumorigenesis.

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