Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Correspondence
  • Published:

Reply to ‘Neutral tumor evolution?’

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

Subjects

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).

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

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

References

  1. Tarabichi, M. et al. Nat. Genet. https://doi.org/10.1038/s41588-018-0258-x (2018).

  2. Williams, M. J., Werner, B., Barnes, C. P., Graham, T. A. & Sottoriva, A. Nat. Genet. 48, 238–244 (2016).

    Article  CAS  Google Scholar 

  3. Williams, M. J. et al. Nat. Genet. 50, 895–903 (2018).

    Article  CAS  Google Scholar 

  4. Sun, R. et al. Nat. Genet. 49, 1015–1024 (2017).

    Article  CAS  Google Scholar 

  5. Wu, C.-I., Wang, H.-Y., Ling, S. & Lu, X. Annu. Rev. Genet. 50, 347–369 (2016).

    Article  CAS  Google Scholar 

  6. Durrett, R. Ann. Appl. Probab. 23, 230–250 (2013).

    Article  Google Scholar 

  7. Kessler, D. A. & Levine, H. Proc. Natl. Acad. Sci. USA 110, 11682–11687 (2013).

    Article  CAS  Google Scholar 

  8. Kessler, D. A. & Levine, H. J. Stat. Phys. 158, 783–805 (2015).

    Article  Google Scholar 

  9. Bozic, I., Gerold, J. M. & Nowak, M. A. PLOS Comput. Biol. 12, e1004731 (2016).

    Article  Google Scholar 

  10. Temko, D. et al. J. Pathol. 245, 283–296 (2018).

    Article  CAS  Google Scholar 

  11. Nik-Zainal, S. et al. Cell 149, 994–1007 (2012).

    Article  CAS  Google Scholar 

  12. Martincorena, I. et al. Cell 171, 1–3 (2017).

    Article  Google Scholar 

  13. Martincorena, I. & Campbell, P. J. Science 349, 1483–1489 (2015).

    Article  CAS  Google Scholar 

  14. Wang, K. et al. Nat. Genet. 46, 573–582 (2014).

    Article  CAS  Google Scholar 

  15. Zapata, L. et al. Genome Biol. 19, 67 (2018).

Download references

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.

Author information

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

Authors
  1. Timon Heide
    View author publications

    Search author on:PubMed Google Scholar

  2. Luis Zapata
    View author publications

    Search author on:PubMed Google Scholar

  3. Marc J. Williams
    View author publications

    Search author on:PubMed Google Scholar

  4. Benjamin Werner
    View author publications

    Search author on:PubMed Google Scholar

  5. Giulio Caravagna
    View author publications

    Search author on:PubMed Google Scholar

  6. Chris P. Barnes
    View author publications

    Search author on:PubMed Google Scholar

  7. Trevor A. Graham
    View author publications

    Search author on:PubMed Google Scholar

  8. Andrea Sottoriva
    View author publications

    Search author on:PubMed Google Scholar

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.

Supplementary information

Supplementary Text and Figures

Supplementary Methods and Supplementary Figures 1 and 2

Reporting Summary

Supplementary Table 1

Supplementary Table 1

Supplementary Table 2

Supplementary Table 2

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41588-018-0256-z

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer