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The evolutionary landscape of colorectal tumorigenesis


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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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.

Data availability

Raw data are available via the European Genome-Phenome Archive ( accession code: EGAS00001003066.


  1. Morson, B. C. Evolution of cancer of the colon and rectum. Cancer 34, 845–849 (1974).

    Article  Google Scholar 

  2. Ashton-Rickardt, P. G. et al. High frequency of APC loss in sporadic colorectal carcinoma due to breaks clustered in 5q21–22. Oncogene 4, 1169–1174 (1989).

    CAS  PubMed  Google Scholar 

  3. Powell, S. M. et al. APC mutations occur early during colorectal tumorigenesis. Nature 359, 235–237 (1992).

    Article  CAS  Google Scholar 

  4. Fearon, E. R. & Vogelstein, B. A genetic model for colorectal tumorigenesis. Cell 61, 759–767 (1990).

    Article  CAS  Google Scholar 

  5. Jones, S. et al. Comparative lesion sequencing provides insights into tumor evolution. Proc. Natl Acad. Sci. USA 105, 4283–4288 (2008).

    Article  CAS  Google Scholar 

  6. Smith, G. et al. Mutations in APC, Kirsten-ras, and p53—alternative genetic pathways to colorectal cancer. Proc. Natl Acad. Sci. USA 99, 9433–9438 (2002).

    Article  CAS  Google Scholar 

  7. Muzny, D. M. et al. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).

    Article  CAS  Google Scholar 

  8. Sottoriva, A. et al. A Big Bang model of human colorectal tumor growth. Nat. Genet. 47, 209–216 (2015).

    Article  CAS  Google Scholar 

  9. Williams, M. J., Werner, B., Barnes, C. P., Graham, T. A. & Sottoriva, A. Identification of neutral tumor evolution across cancer types. Nat. Genet. 48, 238–244 (2016).

    Article  CAS  Google Scholar 

  10. Wright, S. The roles of mutation, inbreeding, crossbreeding and selection in evolution. In Proc. 6th International Congress of Genetics Vol. 1 356–366 (1932).

  11. Yap, T. A., Gerlinger, M., Futreal, P. A., Pusztai, L. & Swanton, C. Intratumor heterogeneity: seeing the wood for the trees. Sci. Transl. Med. 4, 127ps10 (2012).

    Article  Google Scholar 

  12. Blum, M. G. B. & François, O. On statistical tests of phylogenetic tree imbalance: the Sackin and other indices revisited. Math. Biosci. 195, 141–153 (2005).

    Article  Google Scholar 

  13. Fischer, A., Illingworth, C. J., Campbell, P. J. & Mustonen, V. EMu: probabilistic inference of mutational processes and their localization in the cancer genome. Genome Biol. 14, R39 (2013).

    Article  Google Scholar 

  14. Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).

    Article  CAS  Google Scholar 

  15. Katainen, R. et al. CTCF/cohesin-binding sites are frequently mutated in cancer. Nat. Genet. 47, 818–821 (2015).

    Article  CAS  Google Scholar 

  16. Quirke, P. et al. DNA aneuploidy in colorectal adenomas. Br. J. Cancer 53, 477–481 (1986).

    Article  CAS  Google Scholar 

  17. Jones, A. M. et al. Analysis of copy number changes suggests chromosomal instability in a minority of large colorectal adenomas. J. Pathol. 213, 249–256 (2007).

    Article  CAS  Google Scholar 

  18. Wang, H., Liang, L., Fang, J.-Y. & Xu, J. Somatic gene copy number alterations in colorectal cancer: new quest for cancer drivers and biomarkers. Oncogene 35, 2011–2019 (2016).

    Article  CAS  Google Scholar 

  19. Durinck, S. et al. Temporal dissection of tumorigenesis in primary cancers. Cancer Discov. 1, 137–143 (2011).

    Article  CAS  Google Scholar 

  20. Newman, S. et al. The relative timing of mutations in a breast cancer genome. PLoS ONE 8, e64991 (2013).

    Article  CAS  Google Scholar 

  21. Toyota, M. et al. CpG island methylator phenotype in colorectal cancer. Proc. Natl Acad. Sci. USA 96, 8681–8686 (1999).

    Article  CAS  Google Scholar 

  22. Kim, T.-M. et al. Subclonal genomic architectures of primary and metastatic colorectal cancer based on intratumoral genetic heterogeneity. Clin. Cancer Res. 21, 4461–4472 (2015).

    Article  CAS  Google Scholar 

  23. Uchi, R. et al. Integrated multiregional analysis proposing a new model of colorectal cancer evolution. PLoS Genet. 12, e1005778 (2016).

    Article  Google Scholar 

  24. Suzuki, Y. et al. Multiregion ultra-deep sequencing reveals early intermixing and variable levels of intratumoral heterogeneity in colorectal cancer. Mol. Oncol. 11, 124–139 (2017).

    Article  CAS  Google Scholar 

  25. Kim, T.-M. et al. Clonal origins and parallel evolution of regionally synchronous colorectal adenoma and carcinoma. Oncotarget 6, 27725–27735 (2015).

    PubMed  PubMed Central  Google Scholar 

  26. Stachler, M. D. et al. Paired exome analysis of Barrett’s esophagus and adenocarcinoma. Nat. Genet. 47, 1047–1055 (2015).

    Article  CAS  Google Scholar 

  27. Maley, C. C. et al. Genetic clonal diversity predicts progression to esophageal adenocarcinoma. Nat. Genet. 38, 468–473 (2006).

    Article  CAS  Google Scholar 

  28. Ross-Innes, C. S. et al. Whole-genome sequencing provides new insights into the clonal architecture of Barrett’s esophagus and esophageal adenocarcinoma. Nat. Genet. 47, 1038–1046 (2015).

    Article  CAS  Google Scholar 

  29. Andrews, S. FastQC: a quality control tool for high throughput sequence data (Babraham Bioinformatics, 2013);

  30. McKenna, A. et al. The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 20, 1297–1303 (2010).

    Article  CAS  Google Scholar 

  31. Li, H. Aligning sequence reads, clone sequences and assembly contigs with BWA-MEM. Preprint at (2013).

  32. Li, H. et al. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 25, 2078–2079 (2009).

    Article  Google Scholar 

  33. Rimmer, A. et al. Integrating mapping-, assembly- and haplotype-based approaches for calling variants in clinical sequencing applications. Nat Genet. 46, 912–918 (2014).

    Article  CAS  Google Scholar 

  34. Wang, K., Li, M. & Hakonarson, H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 38, e164 (2010).

    Article  Google Scholar 

  35. Cingolani, P. et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin) 6, 80–92 (2012).

    Article  CAS  Google Scholar 

  36. Hasan, M. S., Wu, X. & Zhang, L.Performance evaluation of indel calling tools using real short-read data.Hum. Genom. 9, 20 (2015).

    Article  Google Scholar 

  37. Narzisi, G. et al. Accurate de novo and transmitted indel detection in exome-capture data using microassembly. Nat. Methods 11, 1033–1036 (2014).

    Article  CAS  Google Scholar 

  38. Thorvaldsdóttir, H., Robinson, J. T. & Mesirov, J. P. Integrative Genomics Viewer (IGV): high-performance genomics data visualization and exploration. Brief Bioinform. 14, 178–192 (2013).

    Article  Google Scholar 

  39. Fischer, A., Vázquez-García, I., Illingworth, C. J. R. & Mustonen, V. High-definition reconstruction of clonal composition in cancer. Cell Rep. 7, 1740–1752 (2014).

    Article  CAS  Google Scholar 

  40. Werner, B., Traulsen, A., Sottoriva, A. & Dingli, D. Detecting truly clonal alterations from multi-region profiling of tumours. Sci. Rep. 7, 44991 (2017).

    Article  CAS  Google Scholar 

  41. Nik-Zainal, S. et al. The life history of 21 breast cancers. Cell 149, 994–1007 (2012).

    Article  CAS  Google Scholar 

  42. Paradis, E., Claude, J. & Strimmer, K.APE: analyses of phylogenetics and evolution in R language.Bioinformatics 20, 289–290 (2004).

    Article  CAS  Google Scholar 

  43. Bortolussi, N., Durand, E., Blum, M. & Francois, O. apTreeshape: statistical analysis of phylogenetic tree shape. Bioinformatics 22, 363–364 (2005).

    Article  Google Scholar 

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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).

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Authors and Affiliations




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.

Corresponding authors

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

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Supplementary Information

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

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Supplementary tables 1–7

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Cross, W., Kovac, M., Mustonen, V. et al. The evolutionary landscape of colorectal tumorigenesis. Nat Ecol Evol 2, 1661–1672 (2018).

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