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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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Metastases spreading in a patient with prostate cancer. Five metastases were removed from patient 21 (data from Liu et al. [19]), including three liver metastases (21-2a, 21-2b and 21-2c), one adrenal metastasis (21-3) and one bone metastasis (21-6). (a) Tumor progression tree reconstructed with the TuMult algorithm. The three liver metastases have a longer clonal relationship than the other metastases, all being derived from common precursor 3. (b) Copy number profiles of chromosome 2 in the five metastases. Four common aberrations, delimited by dashed lines, occurred in the common precursor of all the samples. The seven circled aberrations are specific to the three liver metastases, showing these tumors diverged later in the tumor progression tree. These aberrations appeared in common precursor 3, from which the liver metastases are derived.
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Figure 7: Metastases spreading in a patient with prostate cancer. Five metastases were removed from patient 21 (data from Liu et al. [19]), including three liver metastases (21-2a, 21-2b and 21-2c), one adrenal metastasis (21-3) and one bone metastasis (21-6). (a) Tumor progression tree reconstructed with the TuMult algorithm. The three liver metastases have a longer clonal relationship than the other metastases, all being derived from common precursor 3. (b) Copy number profiles of chromosome 2 in the five metastases. Four common aberrations, delimited by dashed lines, occurred in the common precursor of all the samples. The seven circled aberrations are specific to the three liver metastases, showing these tumors diverged later in the tumor progression tree. These aberrations appeared in common precursor 3, from which the liver metastases are derived.

Mentions: For eight patients, the set of metastases included several metastases from the same organ, either at the same anatomic site (liver), or in the same type of organ, but at different locations (lymph nodes and bone metastases). We investigated whether metastases from a given organ were more closely related to each other in the trees than to metastases from other organs. The liver metastases were systematically more closely related to each other than to other metastases. They were always derived from a single precursor (as in patient 21; Figure 7a), with specific events not found in the other metastases (Figure 7b), forming a subtree in the tumor progression tree. This finding is significant, since the probability of observing such a pattern in the three patients by chance, calculated as the proportion of all the possible tree topologies in which liver metastases form a subtree, is only P = 0.003. By contrast, lymph node and bone metastases were often found together with other metastases in the tumor progression trees (Additional file 2). One possible interpretation of the late divergence of liver metastases is that specific alterations are required for liver invasion. Thus, all liver metastases would be likely to arise from a subclone of the prostate tumor with the required alterations. Alternatively, the invasion of the liver by one clone may be the limiting step for metastatic spread in this organ, with all the metastases in the liver resulting from the dissemination of a single clone successfully colonizing the organ. We favor this hypothesis because the alternative explanation would probably result in lymph node and bone metastases being closely related too, and because no organ-specific alterations were identified by Liu et al.


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)

Metastases spreading in a patient with prostate cancer. Five metastases were removed from patient 21 (data from Liu et al. [19]), including three liver metastases (21-2a, 21-2b and 21-2c), one adrenal metastasis (21-3) and one bone metastasis (21-6). (a) Tumor progression tree reconstructed with the TuMult algorithm. The three liver metastases have a longer clonal relationship than the other metastases, all being derived from common precursor 3. (b) Copy number profiles of chromosome 2 in the five metastases. Four common aberrations, delimited by dashed lines, occurred in the common precursor of all the samples. The seven circled aberrations are specific to the three liver metastases, showing these tumors diverged later in the tumor progression tree. These aberrations appeared in common precursor 3, from which the liver metastases are derived.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: Metastases spreading in a patient with prostate cancer. Five metastases were removed from patient 21 (data from Liu et al. [19]), including three liver metastases (21-2a, 21-2b and 21-2c), one adrenal metastasis (21-3) and one bone metastasis (21-6). (a) Tumor progression tree reconstructed with the TuMult algorithm. The three liver metastases have a longer clonal relationship than the other metastases, all being derived from common precursor 3. (b) Copy number profiles of chromosome 2 in the five metastases. Four common aberrations, delimited by dashed lines, occurred in the common precursor of all the samples. The seven circled aberrations are specific to the three liver metastases, showing these tumors diverged later in the tumor progression tree. These aberrations appeared in common precursor 3, from which the liver metastases are derived.
Mentions: For eight patients, the set of metastases included several metastases from the same organ, either at the same anatomic site (liver), or in the same type of organ, but at different locations (lymph nodes and bone metastases). We investigated whether metastases from a given organ were more closely related to each other in the trees than to metastases from other organs. The liver metastases were systematically more closely related to each other than to other metastases. They were always derived from a single precursor (as in patient 21; Figure 7a), with specific events not found in the other metastases (Figure 7b), forming a subtree in the tumor progression tree. This finding is significant, since the probability of observing such a pattern in the three patients by chance, calculated as the proportion of all the possible tree topologies in which liver metastases form a subtree, is only P = 0.003. By contrast, lymph node and bone metastases were often found together with other metastases in the tumor progression trees (Additional file 2). One possible interpretation of the late divergence of liver metastases is that specific alterations are required for liver invasion. Thus, all liver metastases would be likely to arise from a subclone of the prostate tumor with the required alterations. Alternatively, the invasion of the liver by one clone may be the limiting step for metastatic spread in this organ, with all the metastases in the liver resulting from the dissemination of a single clone successfully colonizing the organ. We favor this hypothesis because the alternative explanation would probably result in lymph node and bone metastases being closely related too, and because no organ-specific alterations were identified by Liu et al.

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