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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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Statistical test of in-degree and out-degree of specific alterations.All alterations are ranked by fold change between in-degree and out-degree.DOI:http://dx.doi.org/10.7554/eLife.02869.011
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fig4s1: Statistical test of in-degree and out-degree of specific alterations.All alterations are ranked by fold change between in-degree and out-degree.DOI:http://dx.doi.org/10.7554/eLife.02869.011

Mentions: By considering each single type of mutation affecting the same gene as a distinct and independent node, we construct the comprehensive ISN of CLL mutations (Figure 4A). It is very difficult to capture useful information directly from ISN, while TEDG simplified the topology by capturing the backbone of tumor evolution (Figure 4B). We observe that the monoallelic 13q14 deletion, RB1 deletion, and +12 are significant early events (p-value < 0.01), while the BIRC3 E537fs and the TP53 R248Q are significant late lesions (p-value < 0.05) (Figure 4—figure supplement 1). Also, the analysis of ISN and TEDG shows that different lesions affecting the same gene may occur in distinct branches and stages. For example, mutations K700E and K666E of SF3B1 are late events in cases harboring 13q14 deletion, while mutations R273C of TP53 are late events in cases with +12. Though the sample size prevents statistical considerations, TEDG reveals the H179R and Y234C missense substitutions in TP53 may be early events, while the R248Q, R273C, P152fs, and N239T substitutions are late events.10.7554/eLife.02869.010Figure 4.TEDG analysis of specific genetic lesions.


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)

Statistical test of in-degree and out-degree of specific alterations.All alterations are ranked by fold change between in-degree and out-degree.DOI:http://dx.doi.org/10.7554/eLife.02869.011
© Copyright Policy
Related In: Results  -  Collection

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

fig4s1: Statistical test of in-degree and out-degree of specific alterations.All alterations are ranked by fold change between in-degree and out-degree.DOI:http://dx.doi.org/10.7554/eLife.02869.011
Mentions: By considering each single type of mutation affecting the same gene as a distinct and independent node, we construct the comprehensive ISN of CLL mutations (Figure 4A). It is very difficult to capture useful information directly from ISN, while TEDG simplified the topology by capturing the backbone of tumor evolution (Figure 4B). We observe that the monoallelic 13q14 deletion, RB1 deletion, and +12 are significant early events (p-value < 0.01), while the BIRC3 E537fs and the TP53 R248Q are significant late lesions (p-value < 0.05) (Figure 4—figure supplement 1). Also, the analysis of ISN and TEDG shows that different lesions affecting the same gene may occur in distinct branches and stages. For example, mutations K700E and K666E of SF3B1 are late events in cases harboring 13q14 deletion, while mutations R273C of TP53 are late events in cases with +12. Though the sample size prevents statistical considerations, TEDG reveals the H179R and Y234C missense substitutions in TP53 may be early events, while the R248Q, R273C, P152fs, and N239T substitutions are late events.10.7554/eLife.02869.010Figure 4.TEDG analysis of specific genetic lesions.

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