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Analysis of the copy number profiles of several tumor samples from the same patient reveals the successive steps in tumorigenesis.

Letouzé E, Allory Y, Bollet MA, Radvanyi F, Guyon F - Genome Biol. (2010)

Bottom Line: We present a computational method, TuMult, for reconstructing the sequence of copy number changes driving carcinogenesis, based on the analysis of several tumor samples from the same patient.We demonstrate the reliability of the method with simulated data, and describe applications to three different cancers, showing that TuMult is a valuable tool for the establishment of clonal relationships between tumor samples and the identification of chromosome aberrations occurring at crucial steps in cancer progression.

View Article: PubMed Central - HTML - PubMed

Affiliation: INSERM, UMR-S 973, MTi, Université Paris Diderot - Paris 7, 35 rue Hélène Brion, 75205 Paris Cedex 13, France. eric.letouze@gmail.com

ABSTRACT
We present a computational method, TuMult, for reconstructing the sequence of copy number changes driving carcinogenesis, based on the analysis of several tumor samples from the same patient. We demonstrate the reliability of the method with simulated data, and describe applications to three different cancers, showing that TuMult is a valuable tool for the establishment of clonal relationships between tumor samples and the identification of chromosome aberrations occurring at crucial steps in cancer progression.

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Principle of tumor progression tree reconstruction. (a) CGH log ratio profiles of two bladder tumors from the same patient, with color code as follows: homozygous deletions in blue, losses in green, normal regions in yellow, and gains in red. Chromosomes are delineated by gray vertical lines and a schematic representation of chromosomes and centromeres is drawn below each profile. Chromosome breakpoints common to both samples are indicated by dashed lines, with an arrow representing the sign of each breakpoint. For greater clarity, the common breakpoints on either side of the one-BAC homozygous deletion at 9p21 are not drawn. This common aberration is instead circled in each profile. (b) Tumor progression tree reconstructed for the two samples. Common breakpoints define early aberrations occurring in the common precursor of the two samples. Chromosome aberrations specific to each tumor are placed on subsequent edges.
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Figure 1: Principle of tumor progression tree reconstruction. (a) CGH log ratio profiles of two bladder tumors from the same patient, with color code as follows: homozygous deletions in blue, losses in green, normal regions in yellow, and gains in red. Chromosomes are delineated by gray vertical lines and a schematic representation of chromosomes and centromeres is drawn below each profile. Chromosome breakpoints common to both samples are indicated by dashed lines, with an arrow representing the sign of each breakpoint. For greater clarity, the common breakpoints on either side of the one-BAC homozygous deletion at 9p21 are not drawn. This common aberration is instead circled in each profile. (b) Tumor progression tree reconstructed for the two samples. Common breakpoints define early aberrations occurring in the common precursor of the two samples. Chromosome aberrations specific to each tumor are placed on subsequent edges.

Mentions: Two tumors descended from the same initial cancerous cell generally have a number of genetic alterations in common, these changes having occurred before the separation of the two clones. They also display specific genetic alterations that occurred independently in each clone after their separation. A comparison of the alterations in each clone can thus be used to reconstruct the sequence of chromosomal events giving rise to each tumor (Figure 1). Logically, clones separating later in the tumorigenesis process should have more genetic events in common than those separating earlier in this process. This is the simple reasoning underlying our methodology. The TuMult algorithm reconstructs the tumor lineage tree from the leaves (tumors) to the root (normal cell), by iterative grouping of the two closest nodes in terms of chromosome breakpoints. Simultaneously, the copy number profile of each intermediate node, corresponding to an ancestral tumor clone, is reconstructed at each step of the algorithm (see Materials and methods for details).


Analysis of the copy number profiles of several tumor samples from the same patient reveals the successive steps in tumorigenesis.

Letouzé E, Allory Y, Bollet MA, Radvanyi F, Guyon F - Genome Biol. (2010)

Principle of tumor progression tree reconstruction. (a) CGH log ratio profiles of two bladder tumors from the same patient, with color code as follows: homozygous deletions in blue, losses in green, normal regions in yellow, and gains in red. Chromosomes are delineated by gray vertical lines and a schematic representation of chromosomes and centromeres is drawn below each profile. Chromosome breakpoints common to both samples are indicated by dashed lines, with an arrow representing the sign of each breakpoint. For greater clarity, the common breakpoints on either side of the one-BAC homozygous deletion at 9p21 are not drawn. This common aberration is instead circled in each profile. (b) Tumor progression tree reconstructed for the two samples. Common breakpoints define early aberrations occurring in the common precursor of the two samples. Chromosome aberrations specific to each tumor are placed on subsequent edges.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2926787&req=5

Figure 1: Principle of tumor progression tree reconstruction. (a) CGH log ratio profiles of two bladder tumors from the same patient, with color code as follows: homozygous deletions in blue, losses in green, normal regions in yellow, and gains in red. Chromosomes are delineated by gray vertical lines and a schematic representation of chromosomes and centromeres is drawn below each profile. Chromosome breakpoints common to both samples are indicated by dashed lines, with an arrow representing the sign of each breakpoint. For greater clarity, the common breakpoints on either side of the one-BAC homozygous deletion at 9p21 are not drawn. This common aberration is instead circled in each profile. (b) Tumor progression tree reconstructed for the two samples. Common breakpoints define early aberrations occurring in the common precursor of the two samples. Chromosome aberrations specific to each tumor are placed on subsequent edges.
Mentions: Two tumors descended from the same initial cancerous cell generally have a number of genetic alterations in common, these changes having occurred before the separation of the two clones. They also display specific genetic alterations that occurred independently in each clone after their separation. A comparison of the alterations in each clone can thus be used to reconstruct the sequence of chromosomal events giving rise to each tumor (Figure 1). Logically, clones separating later in the tumorigenesis process should have more genetic events in common than those separating earlier in this process. This is the simple reasoning underlying our methodology. The TuMult algorithm reconstructs the tumor lineage tree from the leaves (tumors) to the root (normal cell), by iterative grouping of the two closest nodes in terms of chromosome breakpoints. Simultaneously, the copy number profile of each intermediate node, corresponding to an ancestral tumor clone, is reconstructed at each step of the algorithm (see Materials and methods for details).

Bottom Line: We present a computational method, TuMult, for reconstructing the sequence of copy number changes driving carcinogenesis, based on the analysis of several tumor samples from the same patient.We demonstrate the reliability of the method with simulated data, and describe applications to three different cancers, showing that TuMult is a valuable tool for the establishment of clonal relationships between tumor samples and the identification of chromosome aberrations occurring at crucial steps in cancer progression.

View Article: PubMed Central - HTML - PubMed

Affiliation: INSERM, UMR-S 973, MTi, Université Paris Diderot - Paris 7, 35 rue Hélène Brion, 75205 Paris Cedex 13, France. eric.letouze@gmail.com

ABSTRACT
We present a computational method, TuMult, for reconstructing the sequence of copy number changes driving carcinogenesis, based on the analysis of several tumor samples from the same patient. We demonstrate the reliability of the method with simulated data, and describe applications to three different cancers, showing that TuMult is a valuable tool for the establishment of clonal relationships between tumor samples and the identification of chromosome aberrations occurring at crucial steps in cancer progression.

Show MeSH
Related in: MedlinePlus