Single-cell sequencing data reveal widespread recurrence and loss of mutational hits in the life histories of tumors

  1. Niko Beerenwinkel1,2
  1. 1Department of Biosystems Science and Engineering, ETH Zurich, Basel, 4058, Switzerland;
  2. 2SIB Swiss Institute of Bioinformatics, Basel, 4058, Switzerland;
  3. 3Department of Computer Science, Princeton University, Princeton, New Jersey 08540, USA
  1. 4 These authors contributed equally to this work.

  • Corresponding author: niko.beerenwinkel{at}bsse.ethz.ch
  • Abstract

    Intra-tumor heterogeneity poses substantial challenges for cancer treatment. A tumor's composition can be deduced by reconstructing its mutational history. Central to current approaches is the infinite sites assumption that every genomic position can only mutate once over the lifetime of a tumor. The validity of this assumption has never been quantitatively assessed. We developed a rigorous statistical framework to test the infinite sites assumption with single-cell sequencing data. Our framework accounts for the high noise and contamination present in such data. We found strong evidence for the same genomic position being mutationally affected multiple times in individual tumors for 11 of 12 single-cell sequencing data sets from a variety of human cancers. Seven cases involved the loss of earlier mutations, five of which occurred at sites unaffected by large-scale genomic deletions. Four cases exhibited a parallel mutation, potentially indicating convergent evolution at the base pair level. Our results refute the general validity of the infinite sites assumption and indicate that more complex models are needed to adequately quantify intra-tumor heterogeneity for more effective cancer treatment.

    Footnotes

    • Received January 16, 2017.
    • Accepted September 20, 2017.

    This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

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