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.
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
- Emmanouil T Dermitzakis, University of Geneva Medical School, Switzerland
© 2014, Wang et al.
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