Wang Shizhi, Ding Bo, Cui Mengjing, Yan Wenjing, Xia Qianqian, Meng Dan, Shen Siyuan, Xie Shuqian, Jin Hua, Zhang Xing
Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China.
Department of Gynecology and Obstetrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
Front Cell Dev Biol. 2021 Nov 15;9:734794. doi: 10.3389/fcell.2021.734794. eCollection 2021.
Fanconi anemia (FA) pathway is a typical and multienzyme-regulated DNA damage repairer that influences the occurrence and development of disease including cancers. Few comprehensive analyses were reported about the role of FA-related genes (FARGs) and their prognostic values in cancers. In this study, a comprehensive pan-cancer analysis on 79 FARGs was performed. According to the correlation analyses between HPV integration sites and FARGs, we found that FARGs played specific and critical roles in HPV-related cancers, especially in cervical cancer (CC). Based on this, a FARGs-associated prognostic risk score (FPS) model was constructed, and subsequently a nomogram model containing the FPS was developed with a good accuracy for CC overall survival (OS) and recurrence-free survival (RFS) outcome prediction. We also used the similar expression pattern of FARGs by consensus clustering analysis to separate the patients into three subgroups that exhibited significant differential OS but not RFS. Moreover, differential expressed genes (DEGs) between the two risk groups or three clusters were identified and immune pathways as well as cell adhesion processes were determined by functional enrichment analysis. Results indicated that FARGs might promote occurrence and development of CC by regulating the immune cells' infiltration and cell adhesion. In addition, through the machine learning models containing decision tree, random forest, naïve bayes, and support vector machine models, screening of important variables on CC prognosis, we finally determined that and were the main elements affecting CC OS, while and were for RFS. Kaplan-Meier analysis revealed that bivariate prediction of CC outcome was reliable. Our study systematically analyzed the prognostic prediction values of FARGs and demonstrated their potential mechanism in CC aggressiveness. Results provided perspective in FA pathway-associated modification and theoretical basis for CC clinical treatments.
范可尼贫血（FA）途径是一种典型的、多酶调节的DNA损伤修复途径，它影响包括癌症在内的疾病的发生和发展。关于FA相关基因（FARGs）在癌症中的作用及其预后价值，鲜有全面的分析报道。在本研究中，我们对79个FARGs进行了全面的泛癌分析。根据HPV整合位点与FARGs之间的相关性分析，我们发现FARGs在HPV相关癌症中发挥着特定且关键的作用，尤其是在宫颈癌（CC）中。基于此，构建了一个FARGs相关的预后风险评分（FPS）模型，随后开发了一个包含FPS的列线图模型，该模型对CC总生存期（OS）和无复发生存期（RFS）结局预测具有良好的准确性。我们还通过共识聚类分析使用FARGs的相似表达模式将患者分为三个亚组，这些亚组表现出显著不同的OS，但RFS无差异。此外，确定了两个风险组或三个聚类之间的差异表达基因（DEGs），并通过功能富集分析确定了免疫途径以及细胞黏附过程。结果表明，FARGs可能通过调节免疫细胞浸润和细胞黏附促进CC的发生和发展。此外，通过包含决策树、随机森林、朴素贝叶斯和支持向量机模型的机器学习模型，筛选出影响CC预后的重要变量，我们最终确定 和 是影响CC OS的主要因素，而 和 是影响RFS的因素。Kaplan-Meier分析表明，CC结局的双变量预测是可靠的。我们的研究系统地分析了FARGs的预后预测价值，并证明了它们在CC侵袭性中的潜在机制。研究结果为FA途径相关的修饰提供了视角，并为CC临床治疗提供了理论依据。
