Tumors are widely recognized to progress through clonal evolution by sequentially acquiring selectively advantageous genetic alterations that significantly contribute to tumorigenesis and thus are termned drivers. Some cancer drivers, such as TP53 point mutation or EGFR copy number gain, provide exceptional fitness gains, which, in time, can be sufficient to trigger the onset of cancer with little or no contribution from additional genetic alterations. These key alterations are called superdrivers. In this study, we employ a Wright-Fisher model to study the interplay between drivers and superdrivers in tumor progression. We demonstrate that the resulting evolutionary dynamics follow global clonal expansions of superdrivers with periodic clonal expansions of drivers. We find that the waiting time to the accumulation of a set of superdrivers and drivers in the tumor cell population can be approximated by the sum of the individual waiting times. Our results suggest that superdriver dynamics dominate over driver dynamics in tumorigenesis. Furthermore, our model allows studying the interplay between superdriver and driver mutations both empirically and theoretically.

中文翻译：

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超级驾驶员突变驱动的克隆进化。

通过顺序地获得选择性地有利于遗传发生的有利的遗传改变，肿瘤被认为通过克隆进化而发展，该遗传改变显着地促进了肿瘤发生，因此被称为驱动因子。某些癌症驱动程序（例如TP53点突变或EGFR拷贝数增加）可提供出色的适应性增加，及时地足以触发癌症的发作，而很少或没有其他遗传改变的贡献。这些关键更改称为超级驱动程序。在这项研究中，我们采用Wright-Fisher模型研究驾驶员和超级驾驶员在肿瘤进展中的相互作用。我们证明，由此产生的进化动力学遵循超级驱动程序的全局克隆扩展以及驱动程序的周期性克隆扩展。我们发现，一组超级驱动程序和多个驱动程序在肿瘤细胞群体中积累的等待时间可以通过各个等待时间的总和来近似。我们的结果表明，在肿瘤发生过程中，超级驾驶员动力学优于驾驶员动力学。此外，我们的模型允许从经验和理论上研究超级驾驶员和驾驶员突变之间的相互作用。