非受体型蛋白酪氨酸磷酸酶12基因在脑胶质瘤中的表达及意义

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目的:基于中国脑胶质瘤基因组图谱计划(CGGA)和癌症基因组图谱计划(TCGA)数据库分析非受体型蛋白酪氨酸磷酸酶12基因(n PTPN12)在脑胶质瘤中的表达和意义。n 方法:回顾性分析CGGA数据库(325例)和TCGA数据库(636例)中脑胶质瘤患者的临床资料和RNA测序数据。分析不同世界卫生组织(WHO)肿瘤级别、四分型亚型、异柠檬酸脱氢酶(n IDH)突变状态、On 6-甲基鸟嘌呤-DNA甲基转移酶(n MGMT)启动子甲基化状态的患者n PTPN12表达量的差异。根据n PTPN12的表达量将患者分为n PTPN12高表达组和n PTPN12低表达组,采用Kaplan-Meier法绘制生存曲线,比较两组患者的生存差异。采用单因素和多因素Cox回归分析法判断n PTPN12对脑胶质瘤患者的预后作用。进一步通过基因本体(GO)功能富集分析及京都基因和基因组百科全书(KEGG)通路富集分析获得基因相关的功能以及有关的通路。n 结果:两数据库中,n PTPN12的表达量均随脑胶质瘤病理级别的升高而升高(均n P<0.01);与n IDH突变型比较,n IDH野生型中n PTPN12表达量升高(均n P<0.01);n MGMT启动子非甲基化者n PTPN12表达量高于n MGMT启动子甲基化者(均n P<0.01);n PTPN12在经典型、间质型、神经元型以及前神经元型中表达量的差异均具有统计学意义,间质型中表达量最高(均n P<0.01)。两数据库中,n PTPN12高表达者均比低表达者的生存期短(均n P<0.01)。两个数据库中,多因素Cox回归分析结果均显示,n PTPN12表达量为脑胶质瘤患者生存期的独立影响因素(CGGA数据库中,n HR=1.433,95%n CI:1.094~1.876,n P=0.009;TCGA数据库中,n HR=1.588,95%n CI:1.018~2.477,n P=0.042)。GO分析结果显示,n PTPN12表达量正相关的基因更多地富集在增殖、凋亡、黏附、蛋白水解、免疫反应、血管生成、药物反应、缺氧反应、肿瘤细胞Gn 2/M期的转化、肿瘤细胞Gn 1/S期的转化等多个与脑胶质瘤恶性进展相关的功能上。KEGG分析结果显示,与n PTPN12表达量呈正相关的基因更多地富集在肿瘤相关通路、PI3K-Akt通路、丝裂原活化蛋白激酶通路、肿瘤坏死因子通路、缺氧诱导因子1通路、p53通路、凋亡通路以及细胞周期通路上。n 结论:不同WHO肿瘤级别的脑胶质瘤患者n PTPN12表达量不同,n PTPN12表达量可独立用于脑胶质瘤患者的预后判断,且与多个脑胶质瘤恶性进展相关的功能和通路有关。n “,”Objective:To analyze the expression and significance of protein tyrosine phosphatase non-receptor type 12 (n PTPN12) in gliomas based on the Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) datasets.n Methods:We retrospectively analyzed the clinical data and RNA sequencing data of glioma patients in the CGGA dataset (325 cases) and TCGA dataset (636 cases). We measured the different expression levels of n PTPN12 in glioma patients with different World Health Organization (WHO) grades, subtypes, isocitrate dehydrogenase(n IDH) mutation status and On 6-meth-ylguanine-DNA methyltransferase(n MGMT) promoter methylation status. According to the expression level of n PTPN12, the patients were divided into n PTPN12 high-expression group and n PTPN12 low-expression group. Kaplan-Meier survival curve was used to compare the survival between the two groups. Univariate and multivariate Cox regression analysis were used to determine the prognostic effect of n PTPN12 in glioma patients. Gene ontology (GO) function enrichment analysis and the Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analysis were further used to analyze the related functions and pathways.n Results:In the two datasets, the expression level of n PTPN12 increased with the increase of the glioma grade (all n P<0.01). The expression level ofn PTPN12 in the n IDH wild type was elevated compared with the n IDH mutant type (all n P<0.01). The expression level ofn PTPN12 in n MGMT promoter unmethylated type was higher than that in n MGMT promoter methylated type (all n P<0.01). The expression level ofn PTPN12 was highest in mesenchymal subtype than the other subtypes (all n P<0.01). In the two datasets, the patients with highn PTPN12 expression had a shorter survival time than those with low n PTPN12 expression (both n P<0.01). The results of multivariate Cox regression analysis showed that the expression level ofn PTPN12 was an independent prognostic factor of patients with gliomas (CGGA dataset, n HR=1.433, 95%n CI: 1.094-1.876, n P=0.009; TCGA dataset, n HR=1.588, 95%n CI: 1.018-2.477, n P=0.042). GO analysis results showed that the positive related genes with n PTPN12 were more enriched in proliferation, apoptosis, adhesion, proteolysis, immune response, angiogenesis, drug response, hypoxia response, tumor cell Gn 2/M phase transformation, tumor cell Gn 1/S phase transformation and many other functions related to the malignant progression of glioma. KEGG analysis results showed that the positively related genes with n PTPN12 were more enriched in tumor related pathways, PI3K-Akt pathway, MAPK pathway, TNF pathway, HIF-1 pathway, p53 pathway, apoptosis pathway and cell cycle pathway.n Conclusion:PTPN12 expression levels vary in patients with different WHO tumor levels. n PTPN12 can be used as an independent prognostic factor for patients with gliomas, and it is associated with multiple functions and pathways related to the malignant progression of gliomas.n
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