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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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Related in: MedlinePlus

Justification of MCF.X-axis indicates fraction of CD19+CD5+ cells assessed by FACS analysis, and y-axis indicates maximal mutation fraction of all targeted driver genes of each sample calculated by different methods. One blue dot represents one sample, and contours indicate the density of dots. A suitable calculation of maximal driver mutation fraction will approximate but not exceed the fraction of cancer nuclei. The upper red line indicates CD19+CD5+ cell fraction, and the lower red line indicates a 20% lower interval of it. Apparently, tumor purities of 55 samples are properly assessed by the Hill function MCF, which is better than both MAF without adjustment (10 samples) and simple piecewise MCF (27 samples).
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fig18: Justification of MCF.X-axis indicates fraction of CD19+CD5+ cells assessed by FACS analysis, and y-axis indicates maximal mutation fraction of all targeted driver genes of each sample calculated by different methods. One blue dot represents one sample, and contours indicate the density of dots. A suitable calculation of maximal driver mutation fraction will approximate but not exceed the fraction of cancer nuclei. The upper red line indicates CD19+CD5+ cell fraction, and the lower red line indicates a 20% lower interval of it. Apparently, tumor purities of 55 samples are properly assessed by the Hill function MCF, which is better than both MAF without adjustment (10 samples) and simple piecewise MCF (27 samples).

Mentions: 4) To further justify the Hill function form of MCF, we have used data from FACS analysis to compare it to more simplistic methods. Particularly, given one sample, the maximal mutation fraction of all drivers is separately calculated based on three approaches: MAF, piecewise MCF, and Hill function MCF. A suitable calculation of this score will approximate but not exceed the fraction of cancer nuclei estimated by FACS analysis of the fraction of CD19+CD5+ cells. The comparison shows that the Hill function form of MCF is more robust to assess the tumor purity (Author Response Image 12).Author response image 13.Comparison of MCF and CCF.


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)

Justification of MCF.X-axis indicates fraction of CD19+CD5+ cells assessed by FACS analysis, and y-axis indicates maximal mutation fraction of all targeted driver genes of each sample calculated by different methods. One blue dot represents one sample, and contours indicate the density of dots. A suitable calculation of maximal driver mutation fraction will approximate but not exceed the fraction of cancer nuclei. The upper red line indicates CD19+CD5+ cell fraction, and the lower red line indicates a 20% lower interval of it. Apparently, tumor purities of 55 samples are properly assessed by the Hill function MCF, which is better than both MAF without adjustment (10 samples) and simple piecewise MCF (27 samples).
© Copyright Policy
Related In: Results  -  Collection

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

fig18: Justification of MCF.X-axis indicates fraction of CD19+CD5+ cells assessed by FACS analysis, and y-axis indicates maximal mutation fraction of all targeted driver genes of each sample calculated by different methods. One blue dot represents one sample, and contours indicate the density of dots. A suitable calculation of maximal driver mutation fraction will approximate but not exceed the fraction of cancer nuclei. The upper red line indicates CD19+CD5+ cell fraction, and the lower red line indicates a 20% lower interval of it. Apparently, tumor purities of 55 samples are properly assessed by the Hill function MCF, which is better than both MAF without adjustment (10 samples) and simple piecewise MCF (27 samples).
Mentions: 4) To further justify the Hill function form of MCF, we have used data from FACS analysis to compare it to more simplistic methods. Particularly, given one sample, the maximal mutation fraction of all drivers is separately calculated based on three approaches: MAF, piecewise MCF, and Hill function MCF. A suitable calculation of this score will approximate but not exceed the fraction of cancer nuclei estimated by FACS analysis of the fraction of CD19+CD5+ cells. The comparison shows that the Hill function form of MCF is more robust to assess the tumor purity (Author Response Image 12).Author response image 13.Comparison of MCF and CCF.

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