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 ‘Revisiting signatures of neutral tumor evolution in the light of complexity of cancer genomic data’

Nature Genetics volume 50, pages 1628–1630 (2018)Cite this article

Subjects

Williams et al. reply — Balaparya and De1 question the applicability of the power-law neutral-evolution model to adequately describe the pattern of subclonal somatic mutations in bulk cancer sequencing data.

The authors’ letter focuses on the issues of the inherent noise in next-generation sequencing data, whereby random sampling of alleles, PCR amplification during library preparation, limited depth sequencing, and subclonal copy number changes may cause considerable uncertainty in variant-allele frequency (VAF) measurement. The authors suggest that these errors lead to VAF measurements that, owing to overdispersion, follow a beta-binomial and not a binomial distribution. We thank Balaparya and De for the insightful comments and address their points in the response below.

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 Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Signatures of neutral evolution are robust to confounding factors in the data.

Data availability

Gastric cancers from ref. 3 and colorectal cancers from ref. 4 were analyzed with our framework in our original manuscript2. The new TCGA pan-cancer analysis is based on publicly available GDC calls that can be downloaded from https://portal.gdc.cancer.gov/ (Supplementary Table 1).

References

  1. Balaparya, A. & De, S. Nat. Genet. https://doi.org/10.1038/s41588-018-0219-4 (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. Wang, K. et al. Nat. Genet. 46, 573–582 (2014).

    Article  CAS  Google Scholar 

  4. Sottoriva, A. et al. Nat. Genet. 47, 209–216 (2015).

    Article  CAS  Google Scholar 

  5. Aran, D., Sirota, M. & Butte, A. J. Nat. Commun. 6, 8971 (2015).

    Article  CAS  Google Scholar 

  6. Forbes, S. A. et al. Nucleic Acids Res. 45 D1, D777–D783 (2017).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  8. Andor, N., Harness, J. V., Müller, S., Mewes, H. W. & Petritsch, C. Bioinformatics 30, 50–60 (2014).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Burrell, R. A., McGranahan, N., Bartek, J. & Swanton, C. Nature 501, 338–345 (2013).

    Article  CAS  Google Scholar 

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). This work was also supported by Wellcome Trust funding to the Centre for Evolution and Cancer (105104/Z/14/Z).

Author information

Authors and Affiliations

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

    Marc J. Williams & Trevor A. Graham

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

    Marc J. Williams & Chris P. Barnes

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

    Marc J. Williams

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

    Benjamin Werner, Timon Heide & Andrea Sottoriva

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

    Chris P. Barnes

Authors
  1. Marc J. Williams
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Benjamin Werner
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Timon Heide
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chris P. Barnes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Trevor A. Graham
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Andrea Sottoriva
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.J.W. performed beta-binomial noise analysis. T.H. performed TCGA classification. All authors participated in the discussion and addressed the critiques. M.J.W., B.W., C.P.B., T.A.G., and A.S. wrote the manuscript.

Corresponding authors

Correspondence to Trevor A. Graham or Andrea Sottoriva.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Williams, M.J., Werner, B., Heide, T. et al. Reply to ‘Revisiting signatures of neutral tumor evolution in the light of complexity of cancer genomic data’. Nat Genet 50, 1628–1630 (2018). https://doi.org/10.1038/s41588-018-0210-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41588-018-0210-0

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