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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 compared to non-mutator pathways in the presence of negative clonal selection.The logarithm of Nrel (equal to the logarithm of Prel), the relative prevalence or efficiency of mutator pathways compared to non-mutator pathways, is plotted as a function of the number of oncogenic mutations required for malignant transformation, for varying values of negative clonal selection. Mutator pathways lead to 50% of clinical cancers when log (Nrel) = 0 (pink line), and are favored for all positive values of log (Nrel) (above pink line). The negative clonal selection parameter NRFLN-D (Nreduced fitness loci net-dominant) is an indicator of the vulnerability of the genome to mutations which may reduce cellular fitness [17]. It consists of the number of loci, in base pairs, single copy mutation of which may reduce fitness of the lineage, where the loci are divided into subclasses, and the number in each subclass is multiplied by the probability that a mutation of it will lead to a fitness reduction as a function of genetic and environmental context. It is varied from 0 (no negative clonal selection, constant fitness, red), to intermediate (NRFLN-D = 9.8×104, green) to high (NRFLN-D = 9.8×105, blue). Low negative clonal selection (NRFLN-D = 9.8×103) is not shown, as it is superimposable on no negative clonal selection for the plotted parameter values. Whereas mutator pathways are favored for 3 or more oncogenic mutations required for transformation at no or intermediate negative clonal selection, under strong negative clonal selection 5 or more oncogenic mutations must be required for transformation before mutator pathways are favored. Calculated using equations [28–30], with the wild type mutation rate kmut = 10−11, the fold increase in mutation rate due to a mutator mutation α = 100, the number of cell generations T = 5000, and the number of loci, mutation of which leads to a mutator mutation, NML = 100.
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pone-0005860-g006: Relative efficiency of mutator compared to non-mutator pathways in the presence of negative clonal selection.The logarithm of Nrel (equal to the logarithm of Prel), the relative prevalence or efficiency of mutator pathways compared to non-mutator pathways, is plotted as a function of the number of oncogenic mutations required for malignant transformation, for varying values of negative clonal selection. Mutator pathways lead to 50% of clinical cancers when log (Nrel) = 0 (pink line), and are favored for all positive values of log (Nrel) (above pink line). The negative clonal selection parameter NRFLN-D (Nreduced fitness loci net-dominant) is an indicator of the vulnerability of the genome to mutations which may reduce cellular fitness [17]. It consists of the number of loci, in base pairs, single copy mutation of which may reduce fitness of the lineage, where the loci are divided into subclasses, and the number in each subclass is multiplied by the probability that a mutation of it will lead to a fitness reduction as a function of genetic and environmental context. It is varied from 0 (no negative clonal selection, constant fitness, red), to intermediate (NRFLN-D = 9.8×104, green) to high (NRFLN-D = 9.8×105, blue). Low negative clonal selection (NRFLN-D = 9.8×103) is not shown, as it is superimposable on no negative clonal selection for the plotted parameter values. Whereas mutator pathways are favored for 3 or more oncogenic mutations required for transformation at no or intermediate negative clonal selection, under strong negative clonal selection 5 or more oncogenic mutations must be required for transformation before mutator pathways are favored. Calculated using equations [28–30], with the wild type mutation rate kmut = 10−11, the fold increase in mutation rate due to a mutator mutation α = 100, the number of cell generations T = 5000, and the number of loci, mutation of which leads to a mutator mutation, NML = 100.

Mentions: The relative importance of mutator pathways increases with increasing number of required oncogenic mutations for malignant transformation, but in contrast to the other cases, the minimal number of oncogenic mutations at which mutator pathways are favored [log (Nrel 1:0)>0] varies depending on the strength of negative clonal selection, as shown in Figure 6 for a fold increase in mutation rate α = 100, a wild type mutation rate kmut = 10−11, and a number of cell generations to cancer T = 5,000. At maximal negative clonal selection, there must be at least 5 oncogenic mutations required for malignant transformation before mutator pathways are favored. Additional more detailed results are given in Supplementary Table S3. In general mutator pathways are favored when 5 or more oncogenic mutations are required for malignant transformation and not favored when 2 or fewer oncogenic mutations are required. Results when 3 or 4 oncogenic mutations are required depend on parameter values.


Mutator mutations enhance tumorigenic efficiency across fitness landscapes.

Beckman RA - PLoS ONE (2009)

Relative efficiency of mutator compared to non-mutator pathways in the presence of negative clonal selection.The logarithm of Nrel (equal to the logarithm of Prel), the relative prevalence or efficiency of mutator pathways compared to non-mutator pathways, is plotted as a function of the number of oncogenic mutations required for malignant transformation, for varying values of negative clonal selection. Mutator pathways lead to 50% of clinical cancers when log (Nrel) = 0 (pink line), and are favored for all positive values of log (Nrel) (above pink line). The negative clonal selection parameter NRFLN-D (Nreduced fitness loci net-dominant) is an indicator of the vulnerability of the genome to mutations which may reduce cellular fitness [17]. It consists of the number of loci, in base pairs, single copy mutation of which may reduce fitness of the lineage, where the loci are divided into subclasses, and the number in each subclass is multiplied by the probability that a mutation of it will lead to a fitness reduction as a function of genetic and environmental context. It is varied from 0 (no negative clonal selection, constant fitness, red), to intermediate (NRFLN-D = 9.8×104, green) to high (NRFLN-D = 9.8×105, blue). Low negative clonal selection (NRFLN-D = 9.8×103) is not shown, as it is superimposable on no negative clonal selection for the plotted parameter values. Whereas mutator pathways are favored for 3 or more oncogenic mutations required for transformation at no or intermediate negative clonal selection, under strong negative clonal selection 5 or more oncogenic mutations must be required for transformation before mutator pathways are favored. Calculated using equations [28–30], with the wild type mutation rate kmut = 10−11, the fold increase in mutation rate due to a mutator mutation α = 100, the number of cell generations T = 5000, and the 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-g006: Relative efficiency of mutator compared to non-mutator pathways in the presence of negative clonal selection.The logarithm of Nrel (equal to the logarithm of Prel), the relative prevalence or efficiency of mutator pathways compared to non-mutator pathways, is plotted as a function of the number of oncogenic mutations required for malignant transformation, for varying values of negative clonal selection. Mutator pathways lead to 50% of clinical cancers when log (Nrel) = 0 (pink line), and are favored for all positive values of log (Nrel) (above pink line). The negative clonal selection parameter NRFLN-D (Nreduced fitness loci net-dominant) is an indicator of the vulnerability of the genome to mutations which may reduce cellular fitness [17]. It consists of the number of loci, in base pairs, single copy mutation of which may reduce fitness of the lineage, where the loci are divided into subclasses, and the number in each subclass is multiplied by the probability that a mutation of it will lead to a fitness reduction as a function of genetic and environmental context. It is varied from 0 (no negative clonal selection, constant fitness, red), to intermediate (NRFLN-D = 9.8×104, green) to high (NRFLN-D = 9.8×105, blue). Low negative clonal selection (NRFLN-D = 9.8×103) is not shown, as it is superimposable on no negative clonal selection for the plotted parameter values. Whereas mutator pathways are favored for 3 or more oncogenic mutations required for transformation at no or intermediate negative clonal selection, under strong negative clonal selection 5 or more oncogenic mutations must be required for transformation before mutator pathways are favored. Calculated using equations [28–30], with the wild type mutation rate kmut = 10−11, the fold increase in mutation rate due to a mutator mutation α = 100, the number of cell generations T = 5000, and the number of loci, mutation of which leads to a mutator mutation, NML = 100.
Mentions: The relative importance of mutator pathways increases with increasing number of required oncogenic mutations for malignant transformation, but in contrast to the other cases, the minimal number of oncogenic mutations at which mutator pathways are favored [log (Nrel 1:0)>0] varies depending on the strength of negative clonal selection, as shown in Figure 6 for a fold increase in mutation rate α = 100, a wild type mutation rate kmut = 10−11, and a number of cell generations to cancer T = 5,000. At maximal negative clonal selection, there must be at least 5 oncogenic mutations required for malignant transformation before mutator pathways are favored. Additional more detailed results are given in Supplementary Table S3. In general mutator pathways are favored when 5 or more oncogenic mutations are required for malignant transformation and not favored when 2 or fewer oncogenic mutations are required. Results when 3 or 4 oncogenic mutations are required depend on parameter values.

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