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Reconstructing complex cancer evolutionary histories from multiple bulk DNA samples using Pairtree

View ORCID ProfileJeff A. Wintersinger, Stephanie M. Dobson, View ORCID ProfileLincoln D. Stein, View ORCID ProfileJohn E. Dick, View ORCID ProfileQuaid D. Morris
doi: https://doi.org/10.1101/2020.11.06.372219
Jeff A. Wintersinger
1Department of Computer Science, University of Toronto, Toronto, ON, Canada
2Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada
3Ontario Institute for Cancer Research, Toronto, ON, Canada
4Vector Institute for Artificial Intelligence, Toronto, ON, Canada
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  • ORCID record for Jeff A. Wintersinger
Stephanie M. Dobson
5Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
6Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
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Lincoln D. Stein
3Ontario Institute for Cancer Research, Toronto, ON, Canada
5Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
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John E. Dick
5Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
6Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
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Quaid D. Morris
1Department of Computer Science, University of Toronto, Toronto, ON, Canada
3Ontario Institute for Cancer Research, Toronto, ON, Canada
4Vector Institute for Artificial Intelligence, Toronto, ON, Canada
5Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
7Memorial Sloan Kettering Cancer Center, New York City, NY, USA
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  • For correspondence: morrisq@mskcc.org
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1 Abstract

Cancers are composed of genetically distinct subpopulations of malignant cells. By sequencing DNA from cancer tissue samples, we can characterize the somatic mutations specific to each population and build clone trees describing the evolutionary ancestry of populations relative to one another. These trees reveal critical points in disease development and inform treatment.

Pairtree is a new method for constructing clone trees using DNA sequencing data from one or more bulk samples of an individual cancer. It uses Bayesian inference to compute posterior distributions over the evolutionary relationships between every pair of identified subpopulations, then uses these distributions in a Markov Chain Monte Carlo algorithm to perform efficient inference of the posterior distribution over clone trees. Unlike existing methods, Pairtree can perform clone tree reconstructions using as many as 100 samples per cancer that reveal 30 or more cell subpopulations. On simulated data, Pairtree is the only method whose performance reliably improves when provided with additional bulk samples from a cancer. This suggests a shortcoming of existing methods, as more samples provide more information, and should always make clone tree reconstruction easier. On 14 B-progenitor acute lymphoblastic leukemias with up to 90 samples from each cancer, Pairtree was the only method that could reproduce or improve upon expert-derived clone tree reconstructions. By scaling to more challenging problems, Pairtree supports new biomedical research applications that can improve our understanding of the natural history of cancer, as well as better illustrate the interplay between cancer, host, and therapeutic interventions. The Pairtree method, along with an interactive visual interface for exploring the clone tree posterior, is available at https://github.com/morrislab/pairtree.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Text edited substantially to improve clarity prior to journal submission.

  • https://github.com/morrislab/pairtree

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 18, 2021.
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Reconstructing complex cancer evolutionary histories from multiple bulk DNA samples using Pairtree
Jeff A. Wintersinger, Stephanie M. Dobson, Lincoln D. Stein, John E. Dick, Quaid D. Morris
bioRxiv 2020.11.06.372219; doi: https://doi.org/10.1101/2020.11.06.372219
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Reconstructing complex cancer evolutionary histories from multiple bulk DNA samples using Pairtree
Jeff A. Wintersinger, Stephanie M. Dobson, Lincoln D. Stein, John E. Dick, Quaid D. Morris
bioRxiv 2020.11.06.372219; doi: https://doi.org/10.1101/2020.11.06.372219

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