The evolution of two mutations during clonal expansion
The evolution of two mutations during clonal expansion
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DOI：
10.1534/genetics.107.078915
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发表时间：
2007-12-01
期刊：
影响因子：
3.3
通讯作者：
Michor, Franziska
中科院分区：
文献类型：
--
作者：
Haeno, Hiroshi;Iwasa, Yoh;Michor, Franziska
Knudson的两次命中假说提出，RB1基因的两个基因变化是视网膜母细胞瘤的限速步骤。在这种儿童眼癌的遗传形式中，在体细胞分裂期间只出现一个突变，而在零星病例中，RB1的两个等位基因在生长的视网膜中都被灭活。散发性视网膜母细胞瘤是一种在细胞群体克隆性扩增过程中积累两个突变的情况。其他例子包括对抗癌联合治疗的耐药性的进化，以及肿瘤生长过程中转移抑制基因的两个等位基因的失活。在本文中，我们考虑指数增长的细胞群体，它们必须进化出两个突变，以(I)逃避治疗，(Ii)向(侵袭性)癌症迈进一步，或(Iii)表现出疾病表型。我们计算种群在达到一定规模之前进化出这两种突变的概率。这一概率取决于两个突变出现的速度；携带无突变、一个突变或两个突变的细胞的生长和死亡率；以及细胞群体的大小。此外，我们还推导出了当达到最终种群规模时携带这两种突变的预期细胞数量的公式。我们的理论建立了对克隆扩张过程中两个模拟的动力学的理解。
Knudson's two-hit hypothesis proposes that two genetic changes ill the RB1 gene are the rate-limiting steps of retinoblastoma. In the inherited form of this childhood eye cancer, only one mutation emerges during somatic cell divisions while in sporadic cases, both alleles of RB1 are inactivated in the growing retina. Sporadic retinoblastoma serves as all example of a situation in which two mutations are accumulated during clonal expansion of a cell population. Other examples include evolution of resistance against anticancer combination therapy and inactivation of both alleles of a metastasis-suppressor gene during tumor growth. In this article, we consider an exponentially growing population of cells that must evolve two in mutations to (i) evade treatment, (ii) make a step toward (invasive) cancer, or (iii) display a disease phenotype. We calculate the probability that the population has evolved both mutations before it reaches a certain size. This probability depends oil the rates at which the two mutations arise; the growth and death rates of cells carrying none, one, or both mutations; and the size the cell population reaches. Further, we develop a formula for the expected number of cells carrying both mutations when the final population size is reached. Our theory establishes an understanding of the dynamics of two imitations during clonal expansion.