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Model-based tumor subclonal reconstruction

View ORCID ProfileGiulio Caravagna, View ORCID ProfileTimon Heide, View ORCID ProfileMarc Williams, View ORCID ProfileLuis Zapata, View ORCID ProfileDaniel Nichol, Ketevan Chkhaidze, View ORCID ProfileWilliam Cross, View ORCID ProfileGeorge D. Cresswell, View ORCID ProfileBenjamin Werner, Ahmet Acar, View ORCID ProfileChris P. Barnes, View ORCID ProfileGuido Sanguinetti, View ORCID ProfileTrevor A. Graham, View ORCID ProfileAndrea Sottoriva
doi: https://doi.org/10.1101/586560
Giulio Caravagna
1Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London SM2 5NG, UK
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  • ORCID record for Giulio Caravagna
Timon Heide
1Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London SM2 5NG, UK
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Marc Williams
2Evolution and Cancer Lab, Barts Cancer Institute, School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
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Luis Zapata
1Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London SM2 5NG, UK
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Daniel Nichol
1Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London SM2 5NG, UK
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Ketevan Chkhaidze
1Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London SM2 5NG, UK
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William Cross
2Evolution and Cancer Lab, Barts Cancer Institute, School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
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George D. Cresswell
1Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London SM2 5NG, UK
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Benjamin Werner
1Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London SM2 5NG, UK
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Ahmet Acar
1Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London SM2 5NG, UK
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Chris P. Barnes
3Department of Cell and Developmental Biology and UCL Genetics Institute, University College London, London WC1E 6BTCL, UK
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Guido Sanguinetti
4School of Informatics, University of Edinburgh, Edinburgh, EH8 9AB
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Trevor A. Graham
2Evolution and Cancer Lab, Barts Cancer Institute, School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK
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  • For correspondence: t.graham@qmul.ac.uk andrea.sottoriva@icr.ac.uk
Andrea Sottoriva
1Evolutionary Genomics and Modelling Lab, Centre for Evolution and Cancer, The Institute of Cancer Research, London SM2 5NG, UK
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  • ORCID record for Andrea Sottoriva
  • For correspondence: t.graham@qmul.ac.uk andrea.sottoriva@icr.ac.uk
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Abstract

The vast majority of cancer next-generation sequencing data consist of bulk samples composed of mixtures of cancer and normal cells. To study tumor evolution, subclonal reconstruction approaches based on machine learning are used to separate subpopulation of cancer cells and reconstruct their ancestral relationships. However, current approaches are entirely data-driven and agnostic to evolutionary theory. We demonstrate that systematic errors occur in subclonal reconstruction if tumor evolution is not accounted for, and that those errors increase when multiple samples are taken from the same tumor. To address this issue, we present a novel approach for model-based subclonal reconstruction that combines data-driven machine learning with evolutionary theory. Using public, synthetic and newly generated data, we show the method is more robust and accurate than current techniques in both single-sample and multi-region sequencing data. With careful data curation and interpretation, we show how the method allows minimizing the confounding factors that affect non-evolutionary methods, leading to a more accurate recovery of the evolutionary history of human tumors.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 26, 2019.
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Model-based tumor subclonal reconstruction
Giulio Caravagna, Timon Heide, Marc Williams, Luis Zapata, Daniel Nichol, Ketevan Chkhaidze, William Cross, George D. Cresswell, Benjamin Werner, Ahmet Acar, Chris P. Barnes, Guido Sanguinetti, Trevor A. Graham, Andrea Sottoriva
bioRxiv 586560; doi: https://doi.org/10.1101/586560
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Model-based tumor subclonal reconstruction
Giulio Caravagna, Timon Heide, Marc Williams, Luis Zapata, Daniel Nichol, Ketevan Chkhaidze, William Cross, George D. Cresswell, Benjamin Werner, Ahmet Acar, Chris P. Barnes, Guido Sanguinetti, Trevor A. Graham, Andrea Sottoriva
bioRxiv 586560; doi: https://doi.org/10.1101/586560

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