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A practical guide to cancer subclonal reconstruction from DNA sequencing

Nature Methods volume 18, pages 144–155 (2021)Cite this article

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Abstract

Subclonal reconstruction from bulk tumor DNA sequencing has become a pillar of cancer evolution studies, providing insight into the clonality and relative ordering of mutations and mutational processes. We provide an outline of the complex computational approaches used for subclonal reconstruction from single and multiple tumor samples. We identify the underlying assumptions and uncertainties in each step and suggest best practices for analysis and quality assessment. This guide provides a pragmatic resource for the growing user community of subclonal reconstruction methods.

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Fig. 1: Standard workflow and input data for subclonal reconstruction.
Fig. 2: Subclonal reconstruction using multiple samples.
Fig. 3: CNA reconstructions and uncertainty from whole-genome duplications.

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Acknowledgements

A.S. was supported by an NSERC CGS. M.T. and P.V.L. are supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202) and the Wellcome Trust (FC001202). M.T. is a postdoctoral fellow supported by the European Union’s Horizon 2020 research and innovation program (Marie Skłodowska-Curie grant agreement no. 747852-SIOMICS). P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation’s support towards the establishment of the Francis Crick Institute. M.N.L. was supported by a Junior Research Fellowship (Trinity College, University of Oxford). P.C.B. was supported by a Terry Fox Research Institute New Investigator Award and a CIHR New Investigator Award. Q.M. is supported by an Associate Investigator Award from the Ontario Institute of Cancer Research and holds a Canada CIFAR AI chair. This work was supported by the NIH/NCI under award numbers P30CA016042 (P.C.B.) and P30-CA008748 (Q.M.), and through support from the ITCR (1U24CA248265-01) to P.C.B.

Author information

Author notes

  1. These authors contributed equally: Maxime Tarabichi, Adriana Salcedo, Amit G. Deshwar, Máire Ni Leathlobhair.

  2. These authors jointly directed this work: David C. Wedge, Peter Van Loo, Quaid D. Morris, Paul C. Boutros.

Authors and Affiliations

  1. The Francis Crick Institute, London, UK

    Maxime Tarabichi & Peter Van Loo

  2. Wellcome Sanger Institute, Hinxton, UK

    Maxime Tarabichi

  3. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada

    Adriana Salcedo & Paul C. Boutros

  4. Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA

    Adriana Salcedo & Paul C. Boutros

  5. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    Adriana Salcedo & Paul C. Boutros

  6. Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA

    Adriana Salcedo & Paul C. Boutros

  7. Ontario Institute for Cancer Research, Toronto, Ontario, Canada

    Adriana Salcedo & Quaid D. Morris

  8. The Edward S. Rogers Sr. Department of Electrical & Computer Engineering, University of Toronto, Toronto, Ontario, Canada

    Amit G. Deshwar

  9. Big Data Institute, University of Oxford, Oxford, UK

    Máire Ni Leathlobhair & David C. Wedge

  10. Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK

    Máire Ni Leathlobhair

  11. Department of Computer Science, University of Toronto, Toronto, Ontario, Canada

    Jeff Wintersinger & Quaid D. Morris

  12. Oxford NIHR Biomedical Research Centre, Oxford, UK

    David C. Wedge

  13. Manchester Cancer Research Centre, University of Manchester, Manchester, UK

    David C. Wedge

  14. Vector Institute, Toronto, Ontario, Canada

    Quaid D. Morris & Paul C. Boutros

  15. Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Quaid D. Morris

  16. Donnelly Centre, University of Toronto, Toronto, Ontario, Canada

    Quaid D. Morris

  17. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada

    Paul C. Boutros

  18. Department of Urology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    Paul C. Boutros

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  1. Maxime Tarabichi
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Contributions

M.T., A.S., A.G.D., M.N.L., J.W., D.C.W., Q.D.M., P.V.L. and P.C.B. wrote the text. D.C.W., Q.D.M., P.V.L. and P.C.B. oversaw the completion of this work.

Corresponding author

Correspondence to Paul C. Boutros.

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Competing interests

P.C.B is a member of the Scientific Advisory Boards of BioSymetrics Inc. and Intersect Diagnostics Inc. M.T., A.S., A.G.D., M.N.L., J.W., D.C.W., Q.D.M., and P.V.L. declare no competing interests.

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Peer review information Nature Methods thanks the anonymous reviewers for their contribution to the peer review of this work. Lin Tang was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Tarabichi, M., Salcedo, A., Deshwar, A.G. et al. A practical guide to cancer subclonal reconstruction from DNA sequencing. Nat Methods 18, 144–155 (2021). https://doi.org/10.1038/s41592-020-01013-2

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