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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.

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Relative efficiency of mutator pathways with negative clonal selection versus magnitude of mutation rate increase.The relative efficiency of mutator compared to non-mutator pathways Nrel is plotted against the logarithm of the fold-increase in mutation rate due to a mutator mutation α, for three α values (20, 100, 1000) at high negative clonal selection (net number of dominant reduced fitness loci NRFLN-D = 9.8×105). In contrast to all models without negative clonal selection, a 100-fold increase in the mutation rate leads to a more efficient mutator pathway than a 1,000-fold increase. Calculated using equations [28–30], with the number of oncogenic mutations required for malignant transformation C = 5; number of cell generations to cancer T = 5000; wild type mutation rate kmut = 10−11; number of loci, mutation of which leads to a mutator mutation, NML = 100.
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pone-0005860-g007: Relative efficiency of mutator pathways with negative clonal selection versus magnitude of mutation rate increase.The relative efficiency of mutator compared to non-mutator pathways Nrel is plotted against the logarithm of the fold-increase in mutation rate due to a mutator mutation α, for three α values (20, 100, 1000) at high negative clonal selection (net number of dominant reduced fitness loci NRFLN-D = 9.8×105). In contrast to all models without negative clonal selection, a 100-fold increase in the mutation rate leads to a more efficient mutator pathway than a 1,000-fold increase. Calculated using equations [28–30], with the number of oncogenic mutations required for malignant transformation C = 5; number of cell generations to cancer T = 5000; wild type mutation rate kmut = 10−11; number of loci, mutation of which leads to a mutator mutation, NML = 100.

Mentions: Whereas in the absence of negative clonal selection, higher values of the fold increase α in mutation rate due to a mutator mutation, number of cell generations T, and wild type mutation rate kmut generally favor mutator mutations, in the presence of negative clonal selection the relative importance of mutator pathways depends on the parameter values in a complex way. Figure 7 depicts the relative prevalence of mutator pathways with initial mutator mutations Nrel 1∶0 as a function of α, for the highest levels of negative clonal selection, with the number of oncogenic mutations required for cancer C = 5, the number of cell generations to cancer T = 5,000, and the wild type mutation rate kmut = 10−11, illustrating the decrease in the relative importance of mutator pathways beyond an optimum. Supplementary Table S3 shows the relative probability of a mutator pathway with an initial mutator mutation compared to no mutator pathway, in the presence of negative clonal selection (Nrel 1∶0, NCS) for numerous combinations of parameter values not shown in the Figures.


Mutator mutations enhance tumorigenic efficiency across fitness landscapes.

Beckman RA - PLoS ONE (2009)

Relative efficiency of mutator pathways with negative clonal selection versus magnitude of mutation rate increase.The relative efficiency of mutator compared to non-mutator pathways Nrel is plotted against the logarithm of the fold-increase in mutation rate due to a mutator mutation α, for three α values (20, 100, 1000) at high negative clonal selection (net number of dominant reduced fitness loci NRFLN-D = 9.8×105). In contrast to all models without negative clonal selection, a 100-fold increase in the mutation rate leads to a more efficient mutator pathway than a 1,000-fold increase. Calculated using equations [28–30], with the number of oncogenic mutations required for malignant transformation C = 5; number of cell generations to cancer T = 5000; wild type mutation rate kmut = 10−11; number of loci, mutation of which leads to a mutator mutation, NML = 100.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2690659&req=5

pone-0005860-g007: Relative efficiency of mutator pathways with negative clonal selection versus magnitude of mutation rate increase.The relative efficiency of mutator compared to non-mutator pathways Nrel is plotted against the logarithm of the fold-increase in mutation rate due to a mutator mutation α, for three α values (20, 100, 1000) at high negative clonal selection (net number of dominant reduced fitness loci NRFLN-D = 9.8×105). In contrast to all models without negative clonal selection, a 100-fold increase in the mutation rate leads to a more efficient mutator pathway than a 1,000-fold increase. Calculated using equations [28–30], with the number of oncogenic mutations required for malignant transformation C = 5; number of cell generations to cancer T = 5000; wild type mutation rate kmut = 10−11; number of loci, mutation of which leads to a mutator mutation, NML = 100.
Mentions: Whereas in the absence of negative clonal selection, higher values of the fold increase α in mutation rate due to a mutator mutation, number of cell generations T, and wild type mutation rate kmut generally favor mutator mutations, in the presence of negative clonal selection the relative importance of mutator pathways depends on the parameter values in a complex way. Figure 7 depicts the relative prevalence of mutator pathways with initial mutator mutations Nrel 1∶0 as a function of α, for the highest levels of negative clonal selection, with the number of oncogenic mutations required for cancer C = 5, the number of cell generations to cancer T = 5,000, and the wild type mutation rate kmut = 10−11, illustrating the decrease in the relative importance of mutator pathways beyond an optimum. Supplementary Table S3 shows the relative probability of a mutator pathway with an initial mutator mutation compared to no mutator pathway, in the presence of negative clonal selection (Nrel 1∶0, NCS) for numerous combinations of parameter values not shown in the Figures.

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