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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.

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Data availability

Raw data are available via the European Genome-Phenome Archive (https://ega-archive.org/) accession code: EGAS00001003066.

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Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Acknowledgements

S.J.L., T.A.G. (A19771) and I.P.M.T. (A27327) are funded by Cancer Research UK. We acknowledge core funding provided to the Wellcome Trust Centre for Human Genetics from the Wellcome Trust (090532/Z/09/Z). T.A.G. and S.J.L. were also supported by the Bowel and Cancer Research small grant scheme. T.A.G. was also supported by the Wellcome Trust (202778/Z/16/Z). V.M. was supported in part by funding from the Wellcome Trust (098051). M. Kovac was supported by the Krebsliga beider Basel (grant no. KLBB-12-2013) and the University of Basel (‘Förderung exzellenter Nachwuchsforschender’). A-M.B. also acknowledges funding from Cancer Research UK (A14895). D.C.W. is supported by the Li Ka Shing Foundation. X.J. and I.P.M.T. are supported by an ERC advanced grant (EVOCAN-340560). The S:CORT study is funded by the MRC and Cancer Research UK. K.H is supported by Krebsliga Zentralschweiz. A.S. is supported by the Wellcome Trust (202778/B/16/Z), Cancer Research UK (A22909) and the Chris Rokos Fellowship in Evolution and Cancer. This work was also supported a Wellcome Trust award to the Centre for Evolution and Cancer (105104/Z/14/Z). J.E.E. was funded by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC). V.H.K. was funded by the Swiss National Science Foundation (P2SKP3_168322 / 1 and P2SKP3_168322 / 2). D.T. acknowledges funding from the EPSRC (grant no.: EP/F500351/1).

Author information

I.P.M.T., T.A.G. and S.J.L. conceived and designed the study. R.G., J.E.E., L.M.W., K.H., S.J.L. and I.P.M.T. provided the samples. H.D., A.-M.B., S.B. and L.C. performed the experiments. W.C., M. Kovac, V.M., P.M., R.A. and D.C.W. performed the bioinformatics analysis. W.C. and D.T. performed the mathematical analysis. C.G., A.R.A. and V.H.K. performed the image analysis. M.J., M.R.-J. and L.M.W. performed the pathology assessment. E.D., T.M. and the S:CORT consortium provided reference data. W.C., M. Kovac, V.M., D.T., R.A., V.H.K., X.J., D.C.W., Y.F., M.Kovacova, S.A., A.S., S.J.L., T.A.G. and I.P.M.T. analysed the data. W.C., A.S., S.J.L., T.A.G. and I.P.M.T. performed the evolutionary analysis. W.C., T.A.G. and I.P.M.T. wrote the manuscript with input from all authors.

Competing interests

The authors declare no competing interests.

Correspondence to Trevor A. Graham or Ian P. M. Tomlinson.

Supplementary information

Supplementary Information

Supplementary figures 1–9; Supplementary modelling; Supplementary table legends

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Supplementary tables

Supplementary tables 1–7

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Further reading

Fig. 1: Mutation burdens in CRAs and CRCs.
Fig. 2: Phylogenetic analysis of CRAs and MSS CRCs.
Fig. 3: CNAs in CRAs and MSS CRCs.
Fig. 4: Geography of CRCs.
Fig. 5: CNA timings.