School of IT Convergence, University of Ulsan, 93 Daehak-ro, Nam-gu, Ulsan, 44610, Republic of Korea.
Faculty of Information Technology, Ton Duc Thang University, Ho Chi Minh City, Vietnam.
BMC Med Genomics. 2020 Feb 20;13(Suppl 4):13. doi: 10.1186/s12920-019-0651-z.
Many previous clinical studies have found that accumulated sequential mutations are statistically related to tumorigenesis. However, they are limited in fully elucidating the significance of the ordered-mutation because they did not focus on the network dynamics. Therefore, there is a pressing need to investigate the dynamics characteristics induced by ordered-mutations.
To quantify the ordered-mutation-inducing dynamics, we defined the mutation-sensitivity and the order-specificity that represent if the network is sensitive against a double knockout mutation and if mutation-sensitivity is specific to the mutation order, respectively, using a Boolean network model.
Through intensive investigations, we found that a signaling network is more sensitive when a double-mutation occurs in the direction order inducing a longer path and a smaller number of paths than in the reverse order. In addition, feedback loops involving a gene pair decreased both the mutation-sensitivity and the order-specificity. Next, we investigated relationships of functionally important genes with ordered-mutation-inducing dynamics. The network is more sensitive to mutations subject to drug-targets, whereas it is less specific to the mutation order. Both the sensitivity and specificity are increased when different-drug-targeted genes are mutated. Further, we found that tumor suppressors can efficiently suppress the amplification of oncogenes when the former are mutated earlier than the latter.
Taken together, our results help to understand the importance of the order of mutations with respect to the dynamical effects in complex biological systems.
许多先前的临床研究发现，累积的序贯突变在统计学上与肿瘤发生有关。然而，由于它们没有集中研究有序突变的网络动力学，因此它们在充分阐明有序突变的意义方面存在局限性。因此，迫切需要研究有序突变引起的动力学特征。
为了量化有序突变诱导的动力学，我们使用布尔网络模型定义了突变敏感性和顺序特异性，分别表示网络对双敲除突变是否敏感，以及突变敏感性是否针对突变顺序。
通过深入研究，我们发现当双突变发生在诱导更长路径和更小路径数量的方向顺序中时，信号网络更敏感。此外，涉及基因对的反馈回路降低了突变敏感性和顺序特异性。接下来，我们研究了功能重要基因与有序突变诱导动力学之间的关系。网络对药物靶标基因的突变更敏感，而对突变顺序的特异性较低。当不同药物靶向基因发生突变时，敏感性和特异性都会增加。此外，我们发现当肿瘤抑制基因比癌基因更早发生突变时，前者可以有效地抑制后者的扩增。
综上所述，我们的结果有助于理解在复杂生物系统中，突变顺序与动力学效应的重要性。
