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

Wang J, Khiabanian H, Rossi D, Fabbri G, Gattei V, Forconi F, Laurenti L, Marasca R, Del Poeta G, Foà R, Pasqualucci L, Gaidano G, Rabadan R - Elife (2014)

Bottom Line: 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.Our results suggest that TEDG may constitute an effective framework to recapitulate the evolutionary history of tumors.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Informatics, Columbia University, New York, United States.

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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Phylogenetic trees of CLL patients.Twenty-one out of all CLL patients contain the change of mutation status during disease progression. The phylogenetic trees are constructed based on mutation status of the driver genes. Green balls are normal cells, while all the others are cancer cells with particular alterations.
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fig12: Phylogenetic trees of CLL patients.Twenty-one out of all CLL patients contain the change of mutation status during disease progression. The phylogenetic trees are constructed based on mutation status of the driver genes. Green balls are normal cells, while all the others are cancer cells with particular alterations.

Mentions: We agree that the construction of phylogenetic trees is a good option to infer temporal orders of gene mutations by assuming common ancestors are early events, but limited to the fact that only very few genes have been considered in this study, it is difficult to reconstruct an accurate phylogenetic tree of patients. To approximate the phylogenetic trees, we define the pairwise distances between samples by considering both the number of common mutations and the number of different mutations, and make use of the complete linkage distance method to construct the phylogenetic trees of wild type cell, tumor cell at diagnosis, and tumor cell at different stages of relapse (Author response image 6). Other methods, such as neighbor-joining and parsimony, produce similar results, as expected from the small number of branches and informative sites (driver mutations that vary within a tumor) and, as described below, branching assessment using bootstrap is generically non-significant.Author response image 7.Change of mutation frequency of patient #1.


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

Wang J, Khiabanian H, Rossi D, Fabbri G, Gattei V, Forconi F, Laurenti L, Marasca R, Del Poeta G, Foà R, Pasqualucci L, Gaidano G, Rabadan R - Elife (2014)

Phylogenetic trees of CLL patients.Twenty-one out of all CLL patients contain the change of mutation status during disease progression. The phylogenetic trees are constructed based on mutation status of the driver genes. Green balls are normal cells, while all the others are cancer cells with particular alterations.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4308685&req=5

fig12: Phylogenetic trees of CLL patients.Twenty-one out of all CLL patients contain the change of mutation status during disease progression. The phylogenetic trees are constructed based on mutation status of the driver genes. Green balls are normal cells, while all the others are cancer cells with particular alterations.
Mentions: We agree that the construction of phylogenetic trees is a good option to infer temporal orders of gene mutations by assuming common ancestors are early events, but limited to the fact that only very few genes have been considered in this study, it is difficult to reconstruct an accurate phylogenetic tree of patients. To approximate the phylogenetic trees, we define the pairwise distances between samples by considering both the number of common mutations and the number of different mutations, and make use of the complete linkage distance method to construct the phylogenetic trees of wild type cell, tumor cell at diagnosis, and tumor cell at different stages of relapse (Author response image 6). Other methods, such as neighbor-joining and parsimony, produce similar results, as expected from the small number of branches and informative sites (driver mutations that vary within a tumor) and, as described below, branching assessment using bootstrap is generically non-significant.Author response image 7.Change of mutation frequency of patient #1.

Bottom Line: 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.Our results suggest that TEDG may constitute an effective framework to recapitulate the evolutionary history of tumors.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Informatics, Columbia University, New York, United States.

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.

Show MeSH
Related in: MedlinePlus