Department of Chemistry, Rice University, Houston, TX, United States.
Center for Theoretical Biological Physics, Rice University, Houston, TX, United States.
Sci Rep. 2019 Dec 12;9(1):18940. doi: 10.1038/s41598-019-55300-w.
Cancer is a genetic disease that results from accumulation of unfavorable mutations. As soon as genetic and epigenetic modifications associated with these mutations become strong enough, the uncontrolled tumor cell growth is initiated, eventually spreading through healthy tissues. Clarifying the dynamics of cancer initiation is thus critically important for understanding the molecular mechanisms of tumorigenesis. Here we present a new theoretical method to evaluate the dynamic processes associated with the cancer initiation. It is based on a discrete-state stochastic description of the formation of tumors as a fixation of cancerous mutations in tissues. Using a first-passage analysis the probabilities for the cancer to appear and the times before it happens, which are viewed as fixation probabilities and fixation times, respectively, are explicitly calculated. It is predicted that the slowest cancer initiation dynamics is observed for neutral mutations, while it is fast for both advantageous and, surprisingly, disadvantageous mutations. The method is applied for estimating the cancer initiation times from experimentally available lifetime cancer risks for different types of cancer. It is found that the higher probability of the cancer to occur does not necessary lead to the faster times of starting the cancer. Our theoretical analysis helps to clarify microscopic aspects of cancer initiation processes.
癌症是一种遗传疾病，源于不利突变的积累。一旦与这些突变相关的遗传和表观遗传修饰变得足够强大，不受控制的肿瘤细胞生长就会被启动，最终扩散到健康组织中。因此，阐明癌症起始的动态过程对于理解肿瘤发生的分子机制至关重要。在这里，我们提出了一种新的理论方法来评估与癌症起始相关的动态过程。它基于肿瘤形成的离散状态随机描述，将其视为组织中癌症突变的固定。使用首次通过分析，明确计算了癌症出现的概率和发生之前的时间，分别将其视为固定概率和固定时间。预测表明，中性突变观察到最慢的癌症起始动力学，而有利和令人惊讶的不利突变则非常快。该方法应用于从不同类型癌症的实验可用终生癌症风险中估计癌症起始时间。结果发现，癌症发生的概率较高不一定导致癌症开始的时间更快。我们的理论分析有助于阐明癌症起始过程的微观方面。
