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Reply to ‘Currently available bulk sequencing data do not necessarily support a model of neutral tumor evolution’

Nature Genetics volume 50, pages 1624–1626 (2018)Cite this article

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Werner et al. reply — In their correspondence, McDonald et al.1 question our assertion that the distribution of mutations in tumor bulk sequencing data suggests an underlying neutral evolutionary process in a proportion of cancers2 and instead propose alternative explanations that incorporate subclonal selection. We agree with the authors’ demonstration that it is possible, in principle, to construct models of selection that produce patterns similar to the neutral model. However, the key issue is whether the proposed models of selection are realistic, meaningful and, most importantly, more appropriate than the null neutral model. Before examining this issue, we first note that we extensively stressed in the original manuscript2 that the majority of cases we examined were not consistent with neutral evolution (~70% appeared non-neutral), and we did specifically cite Gerlinger et al.3 as an example of data dominated by selection2. Our finding that the majority of cancers do show evidence of subclonal selection is consistent with previous literature, including the cases highlighted by McDonald et al.3,4.

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Fig. 1: Sensitivity of the 1/f test to subclone cancer cell fraction.

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Acknowledgements

A.S. is supported by the Chris Rokos Fellowship in Evolution and Cancer and by Cancer Research UK (A22909). T.A.G. is supported by Cancer Research UK (A19771). C.P.B. is supported by the Wellcome Trust (097319/Z/11/Z). B.W. is supported by the Geoffrey W. Lewis Post-Doctoral Training fellowship. A.S. and T.A.G. are jointly supported by the Wellcome Trust (202778/B/16/Z and 202778/Z/16/Z, respectively). This work was also supported by Wellcome Trust funding to the Centre for Evolution and Cancer (105104/Z/14/Z).

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Authors and Affiliations

  1. Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK

    Benjamin Werner & Andrea Sottoriva

  2. Evolution and Cancer Laboratory, Barts Cancer Institute, Queen Marry University of London, London, UK

    Marc J. Williams & Trevor A. Graham

  3. Department of Cell and Developmental Biology, University College London, London, UK

    Marc J. Williams & Chris P. Barnes

  4. Centre for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London, London, UK

    Marc J. Williams

  5. Department of Genetics, Evolution and Environment, University College London, London, UK

    Chris P. Barnes

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  1. Benjamin Werner
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  2. Marc J. Williams
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  4. Trevor A. Graham
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  5. Andrea Sottoriva
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Contributions

B.W. performed mathematical analysis. M.J.W. performed simulation analysis. All authors participated in the discussion, conceived and designed the response, and wrote the manuscript.

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Correspondence to Andrea Sottoriva.

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The authors declare no competing interests.

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Werner, B., Williams, M.J., Barnes, C.P. et al. Reply to ‘Currently available bulk sequencing data do not necessarily support a model of neutral tumor evolution’. Nat Genet 50, 1624–1626 (2018). https://doi.org/10.1038/s41588-018-0235-4

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