Limits...
Mutator mutations enhance tumorigenic efficiency across fitness landscapes.

Beckman RA - PLoS ONE (2009)

Bottom Line: Mutator lineages also risk increased deleterious mutations, leading to extinction, thus providing another counterargument to the mutator hypothesis.Mutator mutations likely occur in a minority of premalignant lesions, but these mutator premalignant lesions are disproportionately likely to develop into malignant tumors.The model explains and predicts important biological observations in bacterial and mouse systems, as well as clinical observations.

View Article: PubMed Central - PubMed

Affiliation: Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ, USA. eniac1@snip.net

ABSTRACT

Background: Tumorigenesis requires multiple genetic changes. Mutator mutations are mutations that increase genomic instability, and according to the mutator hypothesis, accelerate tumorigenesis by facilitating oncogenic mutations. Alternatively, repeated lineage selection and expansion without increased mutation frequency may explain observed cancer incidence. Mutator lineages also risk increased deleterious mutations, leading to extinction, thus providing another counterargument to the mutator hypothesis. Both selection and extinction involve changes in lineage fitness, which may be represented as "trajectories" through a "fitness landscape" defined by genetics and environment.

Methodology/principal findings: Here I systematically analyze the relative efficiency of tumorigenesis with and without mutator mutations by evaluating archetypal fitness trajectories using deterministic and stochastic mathematical models. I hypothesize that tumorigenic mechanisms occur clinically in proportion to their relative efficiency. This work quantifies the relative importance of mutator pathways as a function of experimentally measurable parameters, demonstrating that mutator pathways generally enhance efficiency of tumorigenesis. An optimal mutation rate for tumor evolution is derived, and shown to differ from that for species evolution.

Conclusions/significance: The models address the major counterarguments to the mutator hypothesis, confirming that mutator mechanisms are generally more efficient routes to tumorigenesis than non-mutator mechanisms. Mutator mutations are more likely to occur early, and to occur when more oncogenic mutations are required to create a tumor. Mutator mutations likely occur in a minority of premalignant lesions, but these mutator premalignant lesions are disproportionately likely to develop into malignant tumors. Tumor heterogeneity due to mutator mutations may contribute to therapeutic resistance, and the degree of heterogeneity of tumors may need to be considered when therapeutic strategies are devised. The model explains and predicts important biological observations in bacterial and mouse systems, as well as clinical observations.

Show MeSH

Related in: MedlinePlus

Log(α50%), constant fitness and cooperative lineage expansion models with late mutator mutation.The log of α50%, the minimum fold increase in mutation rate due to a mutator mutation at which mutator pathways contribute to 50% of cancers, plotted as a function of C, the number of oncogenic mutations required for transformation, for the constant fitness model (red), and the cooperative lineage expansion model with late mutator mutation (CLE-LMM), with fitness advantage eR = 1.4 (green) or 2.0 (blue), fitness advantage due to enhanced proliferation eRP = 1.2 (green) or 1.4 (blue), T = 170 cell generations (A) or 5000 cell generations (B). The black horizontal line represents α = 500. Mutator mutations with α≤500 are within the range experimentally demonstrated. Points below the black line represent scenarios where mutator pathways are favored. Mutator pathways are generally favored at constant fitness, progressively with more oncogenic mutations required for malignant transformation. CLE-LMM decreases the degree to which mutator pathways are favored, but this effect lessens with more required oncogenic mutations. When 3–4 oncogenic mutations are required for malignant transformation, mutator pathways are favored at constant fitness, but not for CLE-LMM. In contrast to other cases (Figures 2–3), a larger fitness advantage has a small effect in increasing the influence of late mutator pathways. Mutator pathways are increasingly favored with more cell generations T for all models. Calculated as in reference [15] for the constant fitness case, and using equation [20] for the cooperative lineage expansion cases, with the number of oncogenic mutations required for cooperative fitness increase D = 2 (except for when the number of oncogenic mutations required for malignant transformation C = 2, then D = 1); wild type mutation rate kmut = 10−11; and number of loci, mutation of which leads to a mutator mutation NML = 100. These values are conservative, and higher values would further increase the influence of mutator pathways.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2690659&req=5

pone-0005860-g004: Log(α50%), constant fitness and cooperative lineage expansion models with late mutator mutation.The log of α50%, the minimum fold increase in mutation rate due to a mutator mutation at which mutator pathways contribute to 50% of cancers, plotted as a function of C, the number of oncogenic mutations required for transformation, for the constant fitness model (red), and the cooperative lineage expansion model with late mutator mutation (CLE-LMM), with fitness advantage eR = 1.4 (green) or 2.0 (blue), fitness advantage due to enhanced proliferation eRP = 1.2 (green) or 1.4 (blue), T = 170 cell generations (A) or 5000 cell generations (B). The black horizontal line represents α = 500. Mutator mutations with α≤500 are within the range experimentally demonstrated. Points below the black line represent scenarios where mutator pathways are favored. Mutator pathways are generally favored at constant fitness, progressively with more oncogenic mutations required for malignant transformation. CLE-LMM decreases the degree to which mutator pathways are favored, but this effect lessens with more required oncogenic mutations. When 3–4 oncogenic mutations are required for malignant transformation, mutator pathways are favored at constant fitness, but not for CLE-LMM. In contrast to other cases (Figures 2–3), a larger fitness advantage has a small effect in increasing the influence of late mutator pathways. Mutator pathways are increasingly favored with more cell generations T for all models. Calculated as in reference [15] for the constant fitness case, and using equation [20] for the cooperative lineage expansion cases, with the number of oncogenic mutations required for cooperative fitness increase D = 2 (except for when the number of oncogenic mutations required for malignant transformation C = 2, then D = 1); wild type mutation rate kmut = 10−11; and number of loci, mutation of which leads to a mutator mutation NML = 100. These values are conservative, and higher values would further increase the influence of mutator pathways.

Mentions: Mutator mechanisms predominate in most instances as long as C–D≥3 (see Figure 4 and Supplementary Tables S1 and S2), as judged by the values of α50%. In the case of C–D = 3, for example, α50% ranges from 12 to 252, depending on various parameter values (Supplementary Tables S1 and S2). This range is well within that seen with known mutator mutations. As the number of oncogenic mutations required for cancer after the original fitness increase (C–D) increases further, greater predominance of mutator pathways is expected. For cooperative lineage expansion with C–D<3, non-mutator pathways, or mutator pathways with early mutator mutations, are more likely pathogenic mechanisms.


Mutator mutations enhance tumorigenic efficiency across fitness landscapes.

Beckman RA - PLoS ONE (2009)

Log(α50%), constant fitness and cooperative lineage expansion models with late mutator mutation.The log of α50%, the minimum fold increase in mutation rate due to a mutator mutation at which mutator pathways contribute to 50% of cancers, plotted as a function of C, the number of oncogenic mutations required for transformation, for the constant fitness model (red), and the cooperative lineage expansion model with late mutator mutation (CLE-LMM), with fitness advantage eR = 1.4 (green) or 2.0 (blue), fitness advantage due to enhanced proliferation eRP = 1.2 (green) or 1.4 (blue), T = 170 cell generations (A) or 5000 cell generations (B). The black horizontal line represents α = 500. Mutator mutations with α≤500 are within the range experimentally demonstrated. Points below the black line represent scenarios where mutator pathways are favored. Mutator pathways are generally favored at constant fitness, progressively with more oncogenic mutations required for malignant transformation. CLE-LMM decreases the degree to which mutator pathways are favored, but this effect lessens with more required oncogenic mutations. When 3–4 oncogenic mutations are required for malignant transformation, mutator pathways are favored at constant fitness, but not for CLE-LMM. In contrast to other cases (Figures 2–3), a larger fitness advantage has a small effect in increasing the influence of late mutator pathways. Mutator pathways are increasingly favored with more cell generations T for all models. Calculated as in reference [15] for the constant fitness case, and using equation [20] for the cooperative lineage expansion cases, with the number of oncogenic mutations required for cooperative fitness increase D = 2 (except for when the number of oncogenic mutations required for malignant transformation C = 2, then D = 1); wild type mutation rate kmut = 10−11; and number of loci, mutation of which leads to a mutator mutation NML = 100. These values are conservative, and higher values would further increase the influence of mutator pathways.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2690659&req=5

pone-0005860-g004: Log(α50%), constant fitness and cooperative lineage expansion models with late mutator mutation.The log of α50%, the minimum fold increase in mutation rate due to a mutator mutation at which mutator pathways contribute to 50% of cancers, plotted as a function of C, the number of oncogenic mutations required for transformation, for the constant fitness model (red), and the cooperative lineage expansion model with late mutator mutation (CLE-LMM), with fitness advantage eR = 1.4 (green) or 2.0 (blue), fitness advantage due to enhanced proliferation eRP = 1.2 (green) or 1.4 (blue), T = 170 cell generations (A) or 5000 cell generations (B). The black horizontal line represents α = 500. Mutator mutations with α≤500 are within the range experimentally demonstrated. Points below the black line represent scenarios where mutator pathways are favored. Mutator pathways are generally favored at constant fitness, progressively with more oncogenic mutations required for malignant transformation. CLE-LMM decreases the degree to which mutator pathways are favored, but this effect lessens with more required oncogenic mutations. When 3–4 oncogenic mutations are required for malignant transformation, mutator pathways are favored at constant fitness, but not for CLE-LMM. In contrast to other cases (Figures 2–3), a larger fitness advantage has a small effect in increasing the influence of late mutator pathways. Mutator pathways are increasingly favored with more cell generations T for all models. Calculated as in reference [15] for the constant fitness case, and using equation [20] for the cooperative lineage expansion cases, with the number of oncogenic mutations required for cooperative fitness increase D = 2 (except for when the number of oncogenic mutations required for malignant transformation C = 2, then D = 1); wild type mutation rate kmut = 10−11; and number of loci, mutation of which leads to a mutator mutation NML = 100. These values are conservative, and higher values would further increase the influence of mutator pathways.
Mentions: Mutator mechanisms predominate in most instances as long as C–D≥3 (see Figure 4 and Supplementary Tables S1 and S2), as judged by the values of α50%. In the case of C–D = 3, for example, α50% ranges from 12 to 252, depending on various parameter values (Supplementary Tables S1 and S2). This range is well within that seen with known mutator mutations. As the number of oncogenic mutations required for cancer after the original fitness increase (C–D) increases further, greater predominance of mutator pathways is expected. For cooperative lineage expansion with C–D<3, non-mutator pathways, or mutator pathways with early mutator mutations, are more likely pathogenic mechanisms.

Bottom Line: Mutator lineages also risk increased deleterious mutations, leading to extinction, thus providing another counterargument to the mutator hypothesis.Mutator mutations likely occur in a minority of premalignant lesions, but these mutator premalignant lesions are disproportionately likely to develop into malignant tumors.The model explains and predicts important biological observations in bacterial and mouse systems, as well as clinical observations.

View Article: PubMed Central - PubMed

Affiliation: Simons Center for Systems Biology, Institute for Advanced Study, Princeton, NJ, USA. eniac1@snip.net

ABSTRACT

Background: Tumorigenesis requires multiple genetic changes. Mutator mutations are mutations that increase genomic instability, and according to the mutator hypothesis, accelerate tumorigenesis by facilitating oncogenic mutations. Alternatively, repeated lineage selection and expansion without increased mutation frequency may explain observed cancer incidence. Mutator lineages also risk increased deleterious mutations, leading to extinction, thus providing another counterargument to the mutator hypothesis. Both selection and extinction involve changes in lineage fitness, which may be represented as "trajectories" through a "fitness landscape" defined by genetics and environment.

Methodology/principal findings: Here I systematically analyze the relative efficiency of tumorigenesis with and without mutator mutations by evaluating archetypal fitness trajectories using deterministic and stochastic mathematical models. I hypothesize that tumorigenic mechanisms occur clinically in proportion to their relative efficiency. This work quantifies the relative importance of mutator pathways as a function of experimentally measurable parameters, demonstrating that mutator pathways generally enhance efficiency of tumorigenesis. An optimal mutation rate for tumor evolution is derived, and shown to differ from that for species evolution.

Conclusions/significance: The models address the major counterarguments to the mutator hypothesis, confirming that mutator mechanisms are generally more efficient routes to tumorigenesis than non-mutator mechanisms. Mutator mutations are more likely to occur early, and to occur when more oncogenic mutations are required to create a tumor. Mutator mutations likely occur in a minority of premalignant lesions, but these mutator premalignant lesions are disproportionately likely to develop into malignant tumors. Tumor heterogeneity due to mutator mutations may contribute to therapeutic resistance, and the degree of heterogeneity of tumors may need to be considered when therapeutic strategies are devised. The model explains and predicts important biological observations in bacterial and mouse systems, as well as clinical observations.

Show MeSH
Related in: MedlinePlus