Aspirin and Cancer Prevention in Lynch Syndrome: From Cell to Population Data

描述（由申请人提供）：Lynch综合征患者遗传了几种DNA错配修复（MMR）基因之一的生殖系突变，由于微卫星不稳定性（MSI）的发生，导致结直肠癌的发病时间明显早于散发病例，发病率较高。流行病学数据显示，长期服用阿司匹林可降低Lynch综合征患者的结肠癌发病率。这背后的机制 效果并不完全清楚。据认为，保护是通过COX依赖性和独立的活动来实现的。基本的动力学参数，如细胞的分裂率、死亡率和突变率都受到影响。为了更好地理解保护是如何实现的，重要的是要找出细胞参数的变化如何决定在群体水平上观察到的保护程度。该假设是探讨，在人口水平上观察到的保护程度可以预测的数据，量化阿司匹林如何改变参数相关的进化动力学的细胞。这一假设将用一种跨学科的方法进行检验，这种方法将实验与数学模型相结合，并将细胞动力学数据与人群中的发病率数据联系起来。前两个目标将量化阿司匹林改变与细胞生长和进化相关的一组关键参数的程度。这些包括细胞分裂的速率，细胞死亡的速率，发生遗传变化的速率，修复的概率，修复的平均持续时间等。研究首先在体外环境中开始，然后扩展到小鼠中的人类肿瘤异种移植物，这代表了细胞更复杂的生长环境。随后，细胞动力学的数据将为林奇综合征患者体内致癌作用的数学模型提供信息。该模型将用于生成Lynch综合征患者在存在和不存在阿司匹林治疗的情况下结肠癌的理论年龄-发病率曲线。它将通过将模型应用于流行病学数据来测试该模型是否能够成功地预测观察到的年龄-发病率曲线。该模型将使我们能够确定哪些细胞参数对群体数据中观察到的保护作用贡献最大，并探索提高这种保护水平的可能途径。我们的研究结果的意义，了解阿司匹林介导的保护散发性结直肠癌将探讨通过分析适当的流行病学数据。

DESCRIPTION (provided by applicant): Lynch syndrome patients inherit a germline mutation in one of several DNA mismatch repair (MMR) genes, leading to a significantly earlier onset and a higher penetrance of colorectal cancer than in sporadic cases due to the occurrence of microsatellite instability (MSI). Long term administration of aspirin has been shown to reduce the incidence of colon cancer in Lynch syndrome patients, as documented by epidemiological data. The mechanisms underlying this effect are not fully understood. It is thought that protection is achieved through COX-dependent and independent activities. Basic kinetic parameters, such as the division rate, death rate, and mutation rate of cells have been shown to be affected. In order to better understand how protection is achieved, it is important to find out how changes in cellular parameters determine the degree of protection observed on the population level. The hypothesis is explored that the degree of protection observed on the population level can be predicted from data that quantify how aspirin changes parameters related to the evolutionary dynamics of cells. This hypothesis will be tested with an inter-disciplinary approach that combines experiments with mathematical models and that links data on cellular kinetics with those on incidence in the population. The firs two aims will quantify the extent to which aspirin changes a set of key parameters that are related to the growth and evolution of cells. These include the rate of cell division, the rate of ell death, the rate at which genetic changes are incurred, the probability of repair, the mean duration of repair, etc. This will be done with different cell lines exposed to varying levels of inflammation. The investigation starts first in an in vitro setting and is then extended to human tumor xenografts in mice, which represent a more complex growth environment for the cells. Subsequently, the data on cellular kinetics will inform a mathematical model of in vivo carcinogenesis in Lynch Syndrome patients. The model will be used to generate theoretical age-incidence curves for colon cancer in Lynch syndrome patients in the presence and absence of aspirin treatment. It will test whether the model can successfully predict the observed age-incidence curves through model application to epidemiological data. The model will allow us to determine which cellular parameter(s) contribute the most to the protection observed in the population data, and to explore possible avenues to enhance this level of protection. Implications of our results for understanding aspirin-mediated protection against sporadic colorectal cancer will be explored by analyzing appropriate epidemiological data.