Genetic instability and clonal expansion
Genetic instability and clonal expansion
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DOI：
10.1016/j.jtbi.2005.11.012
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发表时间：
2006-07-07
影响因子：
2
通讯作者：
Iwasa, Yoh
中科院分区：
文献类型：
--
作者：
Nowak, Martin A.;Michor, Franziska;Iwasa, Yoh
肿瘤抑制基因的失活可导致克隆扩增。我们研究了这一过程的进化动力学，并计算了肿瘤抑制基因失活之前基因突变赋予遗传不稳定性的概率。不稳定细胞的克隆扩增速率可能比稳定细胞慢，因为产生致死突变或诱导凋亡的可能性增加。我们表明，克隆扩增期间遗传稳定和不稳定细胞的不同生长速率一般来说只是遗传不稳定的一个小缺点。得出这一结论的直观原因是，细胞出生率显著大于死亡率的强大克隆扩张发生的时间比等待那些允许克隆扩张的突变要快得多。此外，在克隆扩增非常缓慢的特殊情况下，遗传不稳定的细胞在克隆扩增过程中积累额外突变的可能性更高，这赋予了选择性优势。只有当肿瘤抑制基因的失活导致细胞繁殖率的非常小的增加时，克隆扩增才代表遗传不稳定性的主要缺点，而这种增加被不稳定细胞的死亡率增加所抵消。(c)2005爱思唯尔有限公司保留所有权利。
inactivation of tumor suppressor genes can lead to clonal expansion. We study the evolutionary dynamics of this process and calculate the probability that inactivation of a tumor suppressor gene is preceded by mutations in genes that confer genetic instability. Unstable cells might have a slower rate of clonal expansion than stable cells because of an increased probability of generating lethal mutations or inducing apoptosis. We show that the different growth rates of genetically stable and unstable cells during clonal expansion represent, in general, only a small disadvantage for genetic instability. The intuitive reason for this conclusion is that robust clonal expansion, where cellular birth rates are significantly greater than death rates, occurs on a much faster time scale than waiting for those mutations that allow clonal expansion. Moreover, in special cases where clonal expansion is very slow, genetically unstable cells have a higher probability to accumulate additional mutations during clonal expansion that confer a selective advantage. Clonal expansion represents a major disadvantage for genetic instability only when inactivation of the tumor suppressor gene leads to a very small increase of the cellular reproductive rate that is cancelled by the increased mortality of unstable cells. (c) 2005 Elsevier Ltd. All rights reserved.