TY - JOUR TI - Tumor evolutionary directed graphs and the history of chronic lymphocytic leukemia AU - Wang, Jiguang AU - Khiabanian, Hossein AU - Rossi, Davide AU - Fabbri, Giulia AU - Gattei, Valter AU - Forconi, Francesco AU - Laurenti, Luca AU - Marasca, Roberto AU - Del Poeta, Giovanni AU - FoĆ , Robin AU - Pasqualucci, Laura AU - Gaidano, Gianluca AU - Rabadan, Raul A2 - Dermitzakis, Emmanouil T VL - 3 PY - 2014 DA - 2014/12/11 SP - e02869 C1 - eLife 2014;3:e02869 DO - 10.7554/eLife.02869 UR - https://doi.org/10.7554/eLife.02869 AB - 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. KW - tumor evolutionary KW - chronic lymphocytic leukemia KW - next generation sequencing JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -