title: Tumor evolutionary directed graphs and the history of chronic lymphocytic leukemia.
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.
authors.affiliation: Department of Biomedical Informatics, Columbia University, New York, United States.
authors.forename: Jiguang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biomedical Informatics, Columbia University, New York, United States.
authors.forename: Hossein
authors.initials: H
authors.lastname: Khiabanian
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Rossi
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, United States.
authors.forename: Giulia
authors.initials: G
authors.lastname: Fabbri
authors.affiliation: Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, Aviano, Italy.
authors.forename: Valter
authors.initials: V
authors.lastname: Gattei
authors.affiliation: Cancer Sciences Unit, Cancer Research UK Centre, University of Southampton, Southampton, United Kingdom.
authors.forename: Francesco
authors.initials: F
authors.lastname: Forconi
authors.affiliation: Institute of Hematology, Catholic University of the Sacred Heart, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Laurenti
authors.affiliation: Division of Hematology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Marasca
authors.affiliation: Department of Hematology, Tor Vergata University, Rome, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Del Poeta
authors.affiliation: Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.
authors.forename: Robin
authors.initials: R
authors.lastname: Foà
authors.affiliation: Institute for Cancer Genetics, Columbia University, New York, United States.
authors.forename: Laura
authors.initials: L
authors.lastname: Pasqualucci
authors.affiliation: Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Gaidano
authors.affiliation: Department of Biomedical Informatics, Columbia University, New York, United States.
authors.forename: Raul
authors.initials: R
authors.lastname: Rabadan
mesh_terms: D060965:Clonal Evolution; D005787:Gene Frequency; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology
keywords: chronic lymphocytic leukemia; evolutionary biology; genomics; human; human biology; medicine; next generation sequencing; tumor evolutionary