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Reply to ‘Neutral tumor evolution?’

Nature Genetics volume 50, pages 1633–1637 (2018)Cite this article

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Heide et al. reply — We thank Tarabichi and colleagues1 for the constructive criticism of our previous work2. Their critique has four main points that we address below.

In our previous study2, we assessed the cumulative variant allele frequency (VAF) distribution M(f) over the frequency range f = [0.12,0.24] to restrict our analysis to subclonal variants within a range applicable to the diverse datasets that we considered. Tarabichi and colleagues note that tumors with a tetraploid genome will have an additional ‘peak’ of clonal mutations at f ~0.25 (mutations in a single allele, Supplementary Fig. 1a), thus causing incorrect rejection of neutrality (Supplementary Fig. 1b). The integration range that we chose was based on a triploid tumor with read depth of 100×, thereby resulting in an upper threshold of 0.26 (Supplementary Methods). Although this procedure is suitable in most cases, it is not suitable for a tetraploid tumor, thus suggesting that the number of tumors consistent with neutral evolution could be larger than we reported. We show how this problem can be avoided by adjusting the range for tetraploid tumors (Supplementary Fig. 1c).

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Fig. 1: Insights from stochastic simulations of cancer growth.
Fig. 2: Detecting subclonal selection with dN/dS analysis.

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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 a 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). M.J.W. is supported by a Medical Research Council student scholarship.

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Author notes

  1. These authors contributed equally: Timon Heide, Luis Zapata, Marc J. Williams, Benjamin Werner

Authors and Affiliations

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

    Timon Heide, Luis Zapata, Benjamin Werner, Giulio Caravagna & Andrea Sottoriva

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

    Marc J. Williams & Trevor A. Graham

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

    Marc J. Williams

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

    Chris P. Barnes

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

    Chris P. Barnes

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  1. Timon Heide
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Contributions

T.H. performed simulation and bioinformatic analyses. L.Z. performed dN/dS analysis. M.J.W. performed additional simulation analysis. B.W. performed mathematical analysis. G.C. provided expertise on clustering analysis. C.P.B., T.A.G. and A.S. conceived and led the study. All authors addressed the criticism and wrote the response.

Corresponding authors

Correspondence to Trevor A. Graham or Andrea Sottoriva.

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Supplementary Table 1

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Heide, T., Zapata, L., Williams, M.J. et al. Reply to ‘Neutral tumor evolution?’. Nat Genet 50, 1633–1637 (2018). https://doi.org/10.1038/s41588-018-0256-z

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