Mutation-selection networks of cancer initiation: tumor suppressor genes and chromosomal instability
Mutation-selection networks of cancer initiation: tumor suppressor genes and chromosomal instability
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DOI：
10.1016/s0022-5193(03)00120-6
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发表时间：
2003-08-21
影响因子：
2
通讯作者：
Nowak, MA
中科院分区：
文献类型：
--
作者：
Komarova, NL;Sengupta, A;Nowak, MA
在本文中，我们推导出描述癌症形成早期事件的随机突变选择网络的解析解。一个主要的假设是，癌症是在组织区室中开始的，其中只有相对少量的细胞有突变成逃避稳态调节的细胞的风险。在这种情况下，演化动力学可以近似为一个低维随机过程与线性柯尔莫哥洛夫向前方程，可以解析求解。大多数情况下，细胞群体在相关突变方面是同质的。有时，这样的均匀状态由随机隧道连接。对隧道的存在性进行了精确的分析，并计算了隧道的发生率。最后，我们计算了染色体不稳定性（CIN）的条件之前的第一个肿瘤抑制基因的失活。在这种情况下，CIN是一种早期事件，也是癌症进展的驱动力。本文开发的技术可用于研究癌症体细胞进化的任意复杂的突变选择网络。(C)2003爱思唯尔有限公司。保留所有权利。
In this paper, we derive analytic solutions of stochastic mutation-selection networks that describe early events of cancer formation. A main assumption is that cancer is initiated in tissue compartments, where only a relatively small number of cells are at risk of mutating into cells that escape from homeostatic regulation. In this case, the evolutionary dynamics can be approximated by a low-dimensional stochastic process with a linear Kolmogorov forward equation that can be solved analytically. Most of the time, the cell population is homogeneous with respect to relevant mutations. Occasionally, such homogeneous states are connected by stochastic tunnels'. We give a precise analysis of the existence of tunnels and calculate the rate of tunneling. Finally, we calculate the conditions for chromosomal instability (CIN) to precede inactivation of the first tumor suppressor gene. In this case, CIN is an early event and a driving force of cancer progression. The techniques developed in this paper can be used to study arbitrarily complex mutation-selection networks of the somatic evolution of cancer. (C) 2003 Elsevier Ltd. All rights reserved.