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Elevated tolerance to aneuploidy in cancer cells: estimating the fitness effects of chromosome number alterations by in silico modelling of somatic genome evolution.

Valind A, Jin Y, Gisselsson D - PLoS ONE (2013)

Bottom Line: Integrating these data into our models allowed estimation of the fitness reduction resulting from a single chromosome copy number change to an average of ≈30% in normal cells.In comparison, cancer cells showed an average fitness reduction of only 6% (p = 0.0008), indicative of aneuploidy tolerance.Reverse engineering of aneuploid cancer cell development in silico predicted that aneuploidy intolerance is a stronger limiting factor for clonal expansion of aneuploid cells than chromosomal mis-segregation rate.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Genetics, Lund University and Skåne Regional and University Laboratories, Lund, Sweden.

ABSTRACT
An unbalanced chromosome number (aneuploidy) is present in most malignant tumours and has been attributed to mitotic mis-segregation of chromosomes. However, recent studies have shown a relatively high rate of chromosomal mis-segregation also in non-neoplastic human cells, while the frequency of aneuploid cells remains low throughout life in most normal tissues. This implies that newly formed aneuploid cells are subject to negative selection in healthy tissues and that attenuation of this selection could contribute to aneuploidy in cancer. To test this, we modelled cellular growth as discrete time branching processes, during which chromosome gains and losses were generated and their host cells subjected to selection pressures of various magnitudes. We then assessed experimentally the frequency of chromosomal mis-segregation as well as the prevalence of aneuploid cells in human non-neoplastic cells and in cancer cells. Integrating these data into our models allowed estimation of the fitness reduction resulting from a single chromosome copy number change to an average of ≈30% in normal cells. In comparison, cancer cells showed an average fitness reduction of only 6% (p = 0.0008), indicative of aneuploidy tolerance. Simulations based on the combined presence of chromosomal mis-segregation and aneuploidy tolerance reproduced distributions of chromosome aberrations in >400 cancer cases with higher fidelity than models based on chromosomal mis-segregation alone. Reverse engineering of aneuploid cancer cell development in silico predicted that aneuploidy intolerance is a stronger limiting factor for clonal expansion of aneuploid cells than chromosomal mis-segregation rate. In conclusion, our findings indicate that not only an elevated chromosomal mis-segregation rate, but also a generalised tolerance to novel chromosomal imbalances contribute to the genomic landscape of human tumours.

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Clonal expansion in a context of normal chromosome mis-segregation.(A) Evaluation of clonal expansion of cells with trisomy for a single chromosome (+C), set up under similar conditions as described in Figure 8 but with a mis-segregation rate similar to normal fibroblasts (p = 4×10−4), a constant rate of positive selection (Sp) of 50%, and a variable degree of negative selection against aneuploidy (Sn). Parallel simulations were performed with a control population with equal conditions except for an absence of positive selection. (B, C) A clonal expansion resulting in dominance of cells with +C (prevalence >99%) after 1000 generations is observed when Sp> Sn, while Sp = Sn results in variable prevalence of cells with +C, including expansion up to a prevalence of 33% (Sn = 50%:1 in C), expansion followed by regression (Sn = 50%:2 in C), and a lack of clonal expansion (Sn = 50%:3 in C). Each circle in B corresponds to a single run of simulations, with 10 runs per level of Sn, while the red line corresponds to mean results. Red plots in C correspond to prevalence of +C cells under positive selection and blue plots reflect the results of parallel control simulations with Sp = 0; x axes denote mitotic generations.
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pone-0070445-g009: Clonal expansion in a context of normal chromosome mis-segregation.(A) Evaluation of clonal expansion of cells with trisomy for a single chromosome (+C), set up under similar conditions as described in Figure 8 but with a mis-segregation rate similar to normal fibroblasts (p = 4×10−4), a constant rate of positive selection (Sp) of 50%, and a variable degree of negative selection against aneuploidy (Sn). Parallel simulations were performed with a control population with equal conditions except for an absence of positive selection. (B, C) A clonal expansion resulting in dominance of cells with +C (prevalence >99%) after 1000 generations is observed when Sp> Sn, while Sp = Sn results in variable prevalence of cells with +C, including expansion up to a prevalence of 33% (Sn = 50%:1 in C), expansion followed by regression (Sn = 50%:2 in C), and a lack of clonal expansion (Sn = 50%:3 in C). Each circle in B corresponds to a single run of simulations, with 10 runs per level of Sn, while the red line corresponds to mean results. Red plots in C correspond to prevalence of +C cells under positive selection and blue plots reflect the results of parallel control simulations with Sp = 0; x axes denote mitotic generations.

Mentions: Clonal expansion should in theory occur under all conditions where the fitness gain of a certain chromosome alteration outweighs the negative selection against aneuploidy. This infers that clonal expansion of aneuploid cells should be able to occur in conditions also with a normal chromosomal mis-segregation rate if the balance between positive and negative selection acting on aneuploidy was perturbed. To model this situation, we set up a small virtual cell population (1000 cells) that were allowed to proliferate under a constant mis-segregation rate similar to that in fibroblasts (Figure 9A). A constant, high positive selection of 50% for all cells obtaining trisomy for a certain chromosome (+C) was introduced, computed in an identical fashion to the LoVo simulations except for the lower positive selection for a single trisomy in that model. The system was then tested with a span of different negative selection levels against aneuploidy. As expected, simulations where positive selection predominated (Sp> Sn) resulted in a dominance (>99% prevalence) of trisomic cells with an extra copy of chromosome C, after less than 100 generations (Figure 9B and C), while the opposite condition (Sp< Sn) failed to generate clonal expansion of +C cells. Notably, simulations with identical positive and negative selection pressure (Sp = Sn) resulted in an unpredictable system, with the prevalence of +C cells ranging from 0 to 33%, providing a correlate to cytogenetic sub-clonality. In all, these simulations showed that even under chromosomally stable conditions such as in non-neoplastic tissue, and in very small populations, an expansion of aneuploid cells can occur if the aneuploidy in question confers a net positive fitness effect.


Elevated tolerance to aneuploidy in cancer cells: estimating the fitness effects of chromosome number alterations by in silico modelling of somatic genome evolution.

Valind A, Jin Y, Gisselsson D - PLoS ONE (2013)

Clonal expansion in a context of normal chromosome mis-segregation.(A) Evaluation of clonal expansion of cells with trisomy for a single chromosome (+C), set up under similar conditions as described in Figure 8 but with a mis-segregation rate similar to normal fibroblasts (p = 4×10−4), a constant rate of positive selection (Sp) of 50%, and a variable degree of negative selection against aneuploidy (Sn). Parallel simulations were performed with a control population with equal conditions except for an absence of positive selection. (B, C) A clonal expansion resulting in dominance of cells with +C (prevalence >99%) after 1000 generations is observed when Sp> Sn, while Sp = Sn results in variable prevalence of cells with +C, including expansion up to a prevalence of 33% (Sn = 50%:1 in C), expansion followed by regression (Sn = 50%:2 in C), and a lack of clonal expansion (Sn = 50%:3 in C). Each circle in B corresponds to a single run of simulations, with 10 runs per level of Sn, while the red line corresponds to mean results. Red plots in C correspond to prevalence of +C cells under positive selection and blue plots reflect the results of parallel control simulations with Sp = 0; x axes denote mitotic generations.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3722120&req=5

pone-0070445-g009: Clonal expansion in a context of normal chromosome mis-segregation.(A) Evaluation of clonal expansion of cells with trisomy for a single chromosome (+C), set up under similar conditions as described in Figure 8 but with a mis-segregation rate similar to normal fibroblasts (p = 4×10−4), a constant rate of positive selection (Sp) of 50%, and a variable degree of negative selection against aneuploidy (Sn). Parallel simulations were performed with a control population with equal conditions except for an absence of positive selection. (B, C) A clonal expansion resulting in dominance of cells with +C (prevalence >99%) after 1000 generations is observed when Sp> Sn, while Sp = Sn results in variable prevalence of cells with +C, including expansion up to a prevalence of 33% (Sn = 50%:1 in C), expansion followed by regression (Sn = 50%:2 in C), and a lack of clonal expansion (Sn = 50%:3 in C). Each circle in B corresponds to a single run of simulations, with 10 runs per level of Sn, while the red line corresponds to mean results. Red plots in C correspond to prevalence of +C cells under positive selection and blue plots reflect the results of parallel control simulations with Sp = 0; x axes denote mitotic generations.
Mentions: Clonal expansion should in theory occur under all conditions where the fitness gain of a certain chromosome alteration outweighs the negative selection against aneuploidy. This infers that clonal expansion of aneuploid cells should be able to occur in conditions also with a normal chromosomal mis-segregation rate if the balance between positive and negative selection acting on aneuploidy was perturbed. To model this situation, we set up a small virtual cell population (1000 cells) that were allowed to proliferate under a constant mis-segregation rate similar to that in fibroblasts (Figure 9A). A constant, high positive selection of 50% for all cells obtaining trisomy for a certain chromosome (+C) was introduced, computed in an identical fashion to the LoVo simulations except for the lower positive selection for a single trisomy in that model. The system was then tested with a span of different negative selection levels against aneuploidy. As expected, simulations where positive selection predominated (Sp> Sn) resulted in a dominance (>99% prevalence) of trisomic cells with an extra copy of chromosome C, after less than 100 generations (Figure 9B and C), while the opposite condition (Sp< Sn) failed to generate clonal expansion of +C cells. Notably, simulations with identical positive and negative selection pressure (Sp = Sn) resulted in an unpredictable system, with the prevalence of +C cells ranging from 0 to 33%, providing a correlate to cytogenetic sub-clonality. In all, these simulations showed that even under chromosomally stable conditions such as in non-neoplastic tissue, and in very small populations, an expansion of aneuploid cells can occur if the aneuploidy in question confers a net positive fitness effect.

Bottom Line: Integrating these data into our models allowed estimation of the fitness reduction resulting from a single chromosome copy number change to an average of ≈30% in normal cells.In comparison, cancer cells showed an average fitness reduction of only 6% (p = 0.0008), indicative of aneuploidy tolerance.Reverse engineering of aneuploid cancer cell development in silico predicted that aneuploidy intolerance is a stronger limiting factor for clonal expansion of aneuploid cells than chromosomal mis-segregation rate.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Genetics, Lund University and Skåne Regional and University Laboratories, Lund, Sweden.

ABSTRACT
An unbalanced chromosome number (aneuploidy) is present in most malignant tumours and has been attributed to mitotic mis-segregation of chromosomes. However, recent studies have shown a relatively high rate of chromosomal mis-segregation also in non-neoplastic human cells, while the frequency of aneuploid cells remains low throughout life in most normal tissues. This implies that newly formed aneuploid cells are subject to negative selection in healthy tissues and that attenuation of this selection could contribute to aneuploidy in cancer. To test this, we modelled cellular growth as discrete time branching processes, during which chromosome gains and losses were generated and their host cells subjected to selection pressures of various magnitudes. We then assessed experimentally the frequency of chromosomal mis-segregation as well as the prevalence of aneuploid cells in human non-neoplastic cells and in cancer cells. Integrating these data into our models allowed estimation of the fitness reduction resulting from a single chromosome copy number change to an average of ≈30% in normal cells. In comparison, cancer cells showed an average fitness reduction of only 6% (p = 0.0008), indicative of aneuploidy tolerance. Simulations based on the combined presence of chromosomal mis-segregation and aneuploidy tolerance reproduced distributions of chromosome aberrations in >400 cancer cases with higher fidelity than models based on chromosomal mis-segregation alone. Reverse engineering of aneuploid cancer cell development in silico predicted that aneuploidy intolerance is a stronger limiting factor for clonal expansion of aneuploid cells than chromosomal mis-segregation rate. In conclusion, our findings indicate that not only an elevated chromosomal mis-segregation rate, but also a generalised tolerance to novel chromosomal imbalances contribute to the genomic landscape of human tumours.

Show MeSH
Related in: MedlinePlus