Tumor evolutionary directed graphs and the history of chronic lymphocytic leukemia
- Columbia University, United States
- Amedeo Avogadro University of Eastern Piedmont, Italy
- Centro di Riferimento Oncologico, Italy
- University of Southampton, United Kingdom
- Catholic University of the Sacred Heart, Italy
- University of Modena and Reggio Emilia, Italy
- Tor Vergata University, Italy
- 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.
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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
- Emmanouil T Dermitzakis, University of Geneva Medical School, Switzerland
Publication history
- Received: March 24, 2014
- Accepted: December 10, 2014
- Accepted Manuscript published: December 11, 2014 (version 1)
- 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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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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