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Elife. 2014 Dec 11;3. doi: 10.7554/eLife.02869.

Tumor evolutionary directed graphs and the history of chronic lymphocytic leukemia.

Author information

1
Department of Biomedical Informatics, Columbia University, New York, United States.
2
Division of Hematology, Department of Translational Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy.
3
Institute for Cancer Genetics, Columbia University, New York, United States.
4
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, Aviano, Italy.
5
Cancer Sciences Unit, Cancer Research UK Centre, University of Southampton, Southampton, United Kingdom.
6
Institute of Hematology, Catholic University of the Sacred Heart, Rome, Italy.
7
Division of Hematology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy.
8
Department of Hematology, Tor Vergata University, Rome, Italy.
9
Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, 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.

KEYWORDS:

chronic lymphocytic leukemia; evolutionary biology; genomics; human; human biology; medicine; next generation sequencing; tumor evolutionary

PMID:
25496728
PMCID:
PMC4308685
DOI:
10.7554/eLife.02869
[Indexed for MEDLINE]
Free PMC Article

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