Efficiency of carcinogenesis with and without a mutator mutation
Efficiency of carcinogenesis with and without a mutator mutation
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DOI：
10.1073/pnas.0606271103
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发表时间：
2006-09-19
影响因子：
11.1
通讯作者：
Loeb, Lawrence A.
中科院分区：
文献类型：
--
作者：
Beckman, Robert A.;Loeb, Lawrence A.
癌变涉及多种遗传变化的获得，改变各种细胞表型。这些变化发生在人类生命的固定时间内，加速这一过程的机制更有可能导致临床癌症。突变体突变降低了基因组的稳定性，因此加速了随机突变的积累，包括致癌基因和肿瘤抑制基因。然而，如果突变本身不致癌，那么获得该突变将在致癌过程中增加一个额外的、潜在的耗时步骤。我们提出了一个确定性的数学模型，允许在癌变过程中任何时间点发生突变时对癌变效率进行定量预测。通过关注细胞系中具有和不具有突变的途径的概率比率，我们可以确定突变突变在人群中独立于绝对比率的频率或重要性，并规避突变突变对于癌症在人类一生中进化是否是“必要的”问题。我们分析了预测突变体在癌变中的相对贡献的关键参数。如果癌变发生得早，涉及突变的机制更有可能发生。由于初始突变率的增加，由于突变体突变导致突变率的更大倍增长，由于癌变过程中所需步骤的增加，以及由于癌症发展的细胞世代数量的增加，突变体突变在癌变过程中的参与是有利的。
Carcinogenesis involves the acquisition of multiple genetic changes altering various cellular phenotypes. These changes occur within the fixed time period of a human lifespan, and mechanisms that accelerate this process are more likely to result in clinical cancers. Mutator mutations decrease genome stability and, hence, accelerate the accumulation of random mutations, including those in oncogenes and tumor suppressor genes. However, if the mutator mutation is not in itself oncogenic, acquiring that mutation would add an extra, potentially time-consuming step in carcinogenesis. We present a deterministic mathematical model that allows quantitative prediction of the efficiency of carcinogenesis with and without a mutator mutation occurring at any time point in the process. By focusing on the ratio of probabilities of pathways with and without mutator mutations within cell lineages, we can define the frequency or importance of mutator mutations in populations independently of absolute rates and circumvent the question of whether mutator mutations are "necessary" for cancers to evolve within a human lifetime. We analyze key parameters that predict the relative contribution of mutator mutants in carcinogenesis. Mechanisms of carcinogenesis involving mutator mutations are more likely if they occur early. Involvement of mutator mutations in carcinogenesis is favored by an increased initial mutation rate, by greater fold-increase in mutation rate due to the mutator mutation, by increased required steps in carcinogenesis, and by increased number of cell generations to the development of cancer.