基于TCGA数据库初步筛选预测胃癌生存期的基因

doi:10.3760/cma.j.cn371439-20190923-00004

摘要/Abstract

摘要：

目的利用癌症基因组图谱(TCGA)中的大量胃癌基因组数据,在胃癌组织差异表达的基因中挖掘与预后相关的基因。方法在TCGA数据库中下载胃腺癌相关基因芯片数据,经R语言数据预处理及用edgeR对基因表达数据进行差异表达分析,利用R语言对差异基因进行基因本体论(GO)富集及KEGG生物通路分析。多因素逐步回归Cox分析预测影响生存期的基因,利用Kaplan-Meier Plotter(http://Kaplan-Meier Plotter.com)网站对上述得到的基因进行在线生存分析。结果 TCGA数据库中共筛选胃癌标本305个,癌旁组织30个。得到3 231个胃癌差异基因,其中上调2 005个基因,下调1 226个基因。GO富集主要集中于抗原连接、丝氨酸水解酶活性、受体配体活性、丝氨酸型肽酶活性、丝氨酸型内肽酶活性、糖胺聚糖结合、细胞因子活性、激素活性、肽酶抑制剂活性、金属钛酶活性等分子功能。KEGG生物通路分析主要涉及化学致癌物、神经活性受体-配体相互作用、细胞因子-细胞因子受体相互作用、细胞色素P450对有害物质的代谢、蛋白质的消化与吸收、金黄色葡萄球菌感染、视黄醇代谢、药物代谢P450、类固醇激素生物代谢、胰液分泌等。Cox分析显示,基因GPX3和SERPINE1对胃癌患者生存期有显著影响。受试者工作特征曲线分析显示,GPX3和SERPINE1表达量的高低对胃癌患者生存期有一定的预测价值,二者临界值分别为0.46、0.68时,敏感性为60.35%,特异性为82.06%,曲线下面积为0.763(95%CI为0.828~0.936)。Kaplan-Meier分析发现,GPX3(P<0.001)和SERPINE1基因(P=0.001)高表达与胃腺癌不良预后有明显关系。结论 SERPINE1、GPX3基因表达越高,胃癌患者生存期越短,二者可能作为胃癌预测预后的靶点。

关键词: 胃肿瘤, 原癌基因, 预后, 基因本体

Abstract:

Objective To extract the genes associated with prognosis from the differential expressed genes in gastric cancer tissues by using a large number of gastric cancer genome data in the cancer genome atlas (TCGA) database. Methods Gene expression data of gastric adenocarcinoma were downloaded from TCGA database. After R language data preprocessing, edgeR was used to analyze the gene differential expression, and R language was used to identify the significant gene ontology (GO) terms and KEGG pathways in gene differential expression. Multivariate Cox stepwise regression analysis was used to predict the genes that affected survival. Genes obtained above were used for survival analysis online in Kaplan-Meier Plotter website (http://Kaplan-Meier Plotter.com). Results A total of 305 gastric cancer and 30 normal gastric tissues were retrieved in TCGA database, and 3 231 differential genes were screened out, including 2 005 up-regulated genes and 1 226 down-regulated genes. These genes were enriched in GO terms including antigen binding, serine hydrolase activity, receptor ligands activity, serine peptidase activity, serine type endopeptidase activity, glycosaminoglycans binding, cytokine activity, hormone activity, peptidase inhibitor activity, metallopeptidase activity and so on. The genes in KEGG pathway analysis were enriched in chemical carcinogen, neuractive receptor-ligand interaction, cytokine-cytokine receptor interaction, metabolism of xenobiotics by cytochrome P450, protein digestion and absorption, staphylococcus aureus infection, retinol metabolism, drug metabolism P450, steroid hormone metabolism, pancreatic secretion and so on. Cox analysis showed that GPX3 and SERPINE1 had significant effect on the survival of gastric cancer patients. Receiver operating characteristic curve analysis showed that the expressions of GPX3 and SERPINE1 had a certain predictive value for the survival time of gastric cancer patients, when the critical values of GPX3 and SERPINE1 were 0.46 and 0.68 respectively, the sensitivity was 60.35%, the specificity was 82.06%, and the area under the curve was 0.763 (95%CI: 0.828-0.936). Kaplan-Meier analysis showed that the high expressions of GPX3 (P<0.001) and SERPINE1 (P=0.001) were significantly related to the poor prognosis of gastric adenocarcinoma. Conclusion The higher expression of SERPINE1 and GPX3 genes, the shorter survival time of gastric cancer patients. They may be the targets for predicting the prognosis of gastric cancer.

Key words: Stomach neoplasms, Proto-oncogenes, Prognosis, Gene ontology

邹文静, 和水祥, 刘丹, 李旭. 基于TCGA数据库初步筛选预测胃癌生存期的基因[J]. 国际肿瘤学杂志, 2020, 47(4): 211-216.

Zou Wenjing, He Shuixiang, Liu Dan, Li Xu. Screening differential genes and prognostic analysis of gastric cancer based on TCGA database[J]. Journal of International Oncology, 2020, 47(4): 211-216.

图/表 6

图1

图2

图3

图4

图5

图6

参考文献 20

[1]	Zhang Y, Chen W, Wang H , et al. Upregulation of miR-519 enhances radiosensitivity of esophageal squamous cell carcinoma trough targeting PI3K/AKT/mTOR signaling pathway[J]. Cancer Chemother Pharmacol, 2019,84(6):1209-1218. DOI: 10.1007/s00280-019-03922-2. doi: 10.1007/s00280-019-03922-2
[2]	Orditura M, Galizia G, Sforza V , et al. Treatment of gastric cancer[J]. World J Gastroenterol, 2014,20(7):1635-1649. DOI: 10.3748/wjg.v20.i7.1635. doi: 10.3748/wjg.v20.i7.1635
[3]	万晶晶 . 胃癌病因学的研究进展[J]. 医学综述, 2014,20(14):2542-2544. DOI: 10.3969/j.issn.1006-2084.2014.14.018.
[4]	Karimi P, Islami F, Anandasabapathy S , et al. Gastric cancer: descriptive epidemiology, risk factors, screening, and prevention[J]. Cancer Epidemiol Biomarkers Prev, 2014,23(5):700-713. DOI: 10.1158/1055-9965.EPI-13-1057. doi: 10.1158/1055-9965.EPI-13-1057
[5]	Cho YE, Yu LR, Abdelmegeed MA , et al. Apoptosis of enterocytes and nitration of junctional complex proteins promote alcohol-induced gut leakiness and liver injury[J]. J Hepatol, 2018,69(1):142-153. DOI: 10.1016/j.jhep.2018.02.005. doi: 10.1016/j.jhep.2018.02.005
[6]	Zhou C, Pan R, Li B , et al. GPX3 hypermethylation in gastric cancer and its prognostic value in patients aged over 60[J]. Future Oncol, 2019,15(11):1279-1289. DOI: 10.2217/fon-2018-0674. doi: 10.2217/fon-2018-0674
[7]	Vignon C, Georget MT, Levern Y , et al. Bone marrow mesenchymal stromal cells regulate the metabolism of H(2)O(2) in human leukemic cells[J]. Blood, 2010,116(21). DOI: 10.1182/blood.V116.21.1058.1058.
[8]	Zhu X, Wang J, Li L , et al. GPX3 suppresses tumor migration and invasion via the FAK/AKT pathway in esophageal squamous cell carcinoma[J]. Am J Transl Res, 2018,10(6):1908-1920.
[9]	Lin Y, Zhang Y, Chen Y , et al. Promoter methylation and clinical significance of GPX3 in esophageal squamous cell carcinoma[J]. Pathol Res Pract, 2019,215(11):152676. DOI: 10.1016/j.prp.2019.152676. doi: 10.1016/j.prp.2019.152676
[10]	Shaaban Y, Taalab MM, Aref S , et al. The clinical significance of decreased GPX3 expression level in Egyptian AML patients[J]. Clin Lymphoma Myeloma Leuk, 2019,19:S205. DOI: 10.1016/j.clml.2019.07.064.
[11]	Liu Q, Bai W, Huang F , et al. Downregulation of microRNA-196a inhibits stem cell self-renewal ability and stemness in non-small-cell lung cancer through upregulating GPX3 expression[J]. Int J Biochem Cell Biol, 2019,115:105571. DOI: 10.1016/j.biocel.2019.105571. doi: 10.1016/j.biocel.2019.105571
[12]	Worley BL, Kim YS, Mardini J , et al. GPx3 supports ovarian cancer progression by manipulating the extracellular redox environment[J]. Redox Biol, 2019,25:101051. DOI: 10.1016/j.redox.2018.11.009. doi: 10.1016/j.redox.2018.11.009
[13]	Xu B, Bai Z, Yin J , et al. Global transcriptomic analysis identifies SERPINE1 as a prognostic biomarker associated with epithelial-to-mesenchymal transition in gastric cancer[J]. Peer J, 2019,7:e7091. DOI: 10.7717/peerj.7091. doi: 10.7717/peerj.7091
[14]	Couto PP, Bastos-Rodrigues L, Schayek H , et al. Spectrum of germline mutations in smokers and nonsmokers in Brazilian nonsmall-cell lung cancer (NSCLC) patients[J]. Carcinogenesis, 2017,38(11):1112-1118. DOI: 10.1093/carcin/bgx089. doi: 10.1093/carcin/bgx089
[15]	Zeng C, Chen Y . HTR1D, TIMP1, SERPINE1, MMP3 and CNR2 affect the survival of patients with colon adenocarcinoma[J]. Oncol Lett, 2019,18(3):2448-2454. DOI: 10.3892/ol.2019.10545.
[16]	Vachher M, Arora K, Burman A , et al. NAMPT, GRN, and SERPINE1 signature as predictor of disease progression and survival in gliomas[J]. J Cell Biochem, 2020,121(4):3010-3023. DOI: 10.1002/jcb.29560. doi: 10.1002/jcb.v121.4
[17]	Li M, Zhao H, Zhao SG , et al. The HMGA2-IMP2 pathway promotes granulosa cell proliferation in polycystic ovary syndrome[J]. 2019,104(4):1049-1059. DOI: 10.1210/jc.2018-00544.
[18]	沈苗, 钟兴伟 . SERPINE1基因在胃癌中的表达及临床意义[J]. 世界华人消化杂志, 2018,26(31):1818-1824. DOI: 10.11569/wcjd.v26.i31.1818.
[19]	Wu DM, Wang S, Wen X, et al. MircoRNA-1275 promotes proliferation, invasion and migration of glioma cells via SERPINE1[J]. J Cell Mol Med, 2018,22(10):4963-4974. DOI: 10.1111/jcmm.13760. doi: 10.1111/jcmm.13760
[20]	Sang Y, Chen MY, Luo D , et al. TEL2 suppresses metastasis by down-regulating SERPINE1 in nasopharyngeal carcinoma[J]. Oncotarget, 2015,6(30):29240-29253. DOI: 10.18632/oncotarget.5074. doi: 10.18632/oncotarget.v6i30