Tumor evolutionary directed graphs and the history of chronic lymphocytic leukemia

  1. Jiguang Wang
  2. Hossein Khiabanian
  3. Davide Rossi
  4. Giulia Fabbri
  5. Valter Gattei
  6. Francesco Forconi
  7. Luca Laurenti
  8. Roberto Marasca
  9. Giovanni Del Poeta
  10. Robin Foà
  11. Laura Pasqualucci
  12. Gianluca Gaidano
  13. Raul Rabadan  Is a corresponding author
  1. Columbia University, United States
  2. Amedeo Avogadro University of Eastern Piedmont, Italy
  3. Centro di Riferimento Oncologico, Italy
  4. University of Southampton, United Kingdom
  5. Catholic University of the Sacred Heart, Italy
  6. University of Modena and Reggio Emilia, Italy
  7. Tor Vergata University, Italy
  8. Sapienza University, Italy

Abstract

Cancer is a clonal evolutionary process, caused by successive accumulation of genetic alterations providing milestones of tumor initiation, progression, dissemination and/or resistance to certain therapeutic regimes. To unravel these milestones we propose a framework, tumor evolutionary directed graphs (TEDG), which is able to characterize the history of genetic alterations by integrating longitudinal and cross-sectional genomic data. We applied TEDG to a chronic lymphocytic leukemia (CLL) cohort of 70 patients spanning 12 years, and show that: (a) the evolution of CLL follows a time-ordered process represented as a global flow in TEDG that proceeds from initiating events to late events; (b) there are two distinct and mutually exclusive evolutionary paths of CLL evolution; (c) higher fitness clones are present in later stages of the disease, indicating a progressive clonal replacement with more aggressive clones. Our results suggest that TEDG may constitute an effective framework to recapitulate the evolutionary history of tumors.

Article and author information

Author details

  1. Jiguang Wang

    Department of Biomedical Informatics, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Hossein Khiabanian

    Department of Biomedical Informatics, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Davide Rossi

    Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
    Competing interests
    The authors declare that no competing interests exist.
  4. Giulia Fabbri

    Institute for Cancer Genetics, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Valter Gattei

    Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, Aviano, Italy
    Competing interests
    The authors declare that no competing interests exist.
  6. Francesco Forconi

    Cancer Sciences Unit, Cancer Research UK Centre, University of Southampton, Southampton, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Luca Laurenti

    Institute of Hematology, Catholic University of the Sacred Heart, Rome, Italy
    Competing interests
    The authors declare that no competing interests exist.
  8. Roberto Marasca

    DIvision of Hematology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy
    Competing interests
    The authors declare that no competing interests exist.
  9. Giovanni Del Poeta

    Department of Hematology, Tor Vergata University, Rome, Italy
    Competing interests
    The authors declare that no competing interests exist.
  10. Robin Foà

    Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy
    Competing interests
    The authors declare that no competing interests exist.
  11. Laura Pasqualucci

    Institute for Cancer Genetics, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Gianluca Gaidano

    Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy
    Competing interests
    The authors declare that no competing interests exist.
  13. Raul Rabadan

    Department of Biomedical Informatics, Columbia University, New York, United States
    For correspondence
    rabadan@dbmi.columbia.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Human subjects: The study was approved by the institutional ethical committee of the Azienda Ospedaliero-Universiataria Maggiore della Carita di Novara affiliated with the Amedeo Avogadro University of Eastern Piedmont, Novara, Italy (Protocol Code 59/CE; Study Number CE 8/11). Patients provided informed consent in accordance with local IRB requirements and Declaration of Helsinki

Reviewing Editor

  1. Emmanouil T Dermitzakis, University of Geneva Medical School, Switzerland

Publication history

  1. Received: March 24, 2014
  2. Accepted: December 10, 2014
  3. Accepted Manuscript published: December 11, 2014 (version 1)
  4. Version of Record published: January 28, 2015 (version 2)

Copyright

© 2014, Wang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Jiguang Wang
  2. Hossein Khiabanian
  3. Davide Rossi
  4. Giulia Fabbri
  5. Valter Gattei
  6. Francesco Forconi
  7. Luca Laurenti
  8. Roberto Marasca
  9. Giovanni Del Poeta
  10. Robin Foà
  11. Laura Pasqualucci
  12. Gianluca Gaidano
  13. Raul Rabadan
(2014)
Tumor evolutionary directed graphs and the history of chronic lymphocytic leukemia
eLife 3:e02869.
https://doi.org/10.7554/eLife.02869
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