Yu Chong, Wang Jin
Department of Statistics, Jilin University of Finance and Economics, Changchun, Jilin, China.
Department of Chemistry and of Physics and Astronomy, State University of New York at Stony Brook, Stony Brook, NY, United States.
Front Oncol. 2022 May 3;12:853768. doi: 10.3389/fonc.2022.853768. eCollection 2022.
Gastric cancer is a daunting disease with a tragic impact on global health. It is the fourth most common cancer and has become the second most frequent cause of cancer death in recent times. According to the Lauren classification, gastric cancer can be classified into two types: intestinal and diffuse. Intestinal-type gastric cancer (IGC) is more common in elderly people, and atrophic gastritis (AG) and intestinal metaplasia (IM) have been proven to be the main premalignant causes of intestinal-type gastric cancer. In turn, infection has been identified as the most significant cause of AG and IM. In this study, we determine the mechanism of IGC progression and how infection induces IGC. Through researching the relevant literature, we identified the key genes associated with gastric cancer and the specific genes associated with IGC. We then use hese genes to build up a gene regulatory network for IGC. Based on this gene regulatory network, we quantify the IGC landscape. Within this landscape, there are three stable states, which are classified as the normal, AG, and gastric cancer states. Through landscape topography, we can determine the biological features and progression process of IGC. To investigate the influence of infection on IGC, we simulated different degrees of infection. As the infection becomes more serious, the landscape topography changes accordingly. A fourth state, named the intestinal metaplasia (IM) state, emerges on the landscape and is associated with a very high risk of developing gastric cancer. The emergence of this state is due to the interactions/regulations among genes. Through variations in the landscape topography, we can determine the influence of infection on IGC. Finally, we use global sensitivity analysis to research the regulations most sensitive to IGC prevention or therapies. This study presents a new approach and a novel model with which to explore the mechanism of IGC. The simulations of different degrees of infection can provide us with a systematic view of IGC progression. The key regulations found can give us some insight and guidance for clinical trials and experimental studies.
胃癌是一种令人生畏的疾病，对全球健康产生了悲惨影响。它是第四大常见癌症，近年来已成为第二大常见癌症死亡原因。根据劳伦分类法，胃癌可分为两种类型：肠型和弥漫型。肠型胃癌（IGC）在老年人中更为常见，萎缩性胃炎（AG）和肠化生（IM）已被证明是肠型胃癌的主要癌前病因。反过来，感染已被确定为AG和IM的最主要病因。在本研究中，我们确定了IGC进展的机制以及感染如何诱发IGC。通过研究相关文献，我们确定了与胃癌相关的关键基因以及与IGC相关的特定基因。然后我们使用这些基因构建了一个IGC的基因调控网络。基于这个基因调控网络，我们量化了IGC格局。在这个格局中，有三种稳定状态，分别被归类为正常、AG和胃癌状态。通过格局地形学，我们可以确定IGC的生物学特征和进展过程。为了研究感染对IGC的影响，我们模拟了不同程度的感染。随着感染变得更加严重，格局地形学相应地发生变化。格局上出现了第四种状态，称为肠化生（IM）状态，并且与患胃癌的非常高风险相关。这种状态的出现是由于基因之间的相互作用/调控。通过格局地形学的变化，我们可以确定感染对IGC的影响。最后，我们使用全局敏感性分析来研究对IGC预防或治疗最敏感的调控。本研究提出了一种探索IGC机制的新方法和新模型。不同程度感染的模拟可以为我们提供IGC进展的系统观点。发现的关键调控可以为我们的临床试验和实验研究提供一些见解和指导。
