细胞周期蛋白依赖性激酶抑制蛋白2A基因拷贝数变异及其与胰腺癌患者预后的关系

Relation of copy number variation of cyclin-dependent kinase inhibitor 2A gene with prognosis of patients with pancreatic cancer

目的:探讨细胞周期蛋白依赖性激酶抑制蛋白2A(CDKN2A)基因在胰腺癌中的拷贝数变异(CNV)情况及其与胰腺癌患者预后的关系。方法:利用癌症基因组图谱(TCGA)数据库CNV与RNA Seq V2数据分析CDKN2A基因CNV与其mRNA表达水平的相关性,以及CDKN2A基因CNV对其他基因表达的影响。通过比对TCGA数据库及GTEx数据库比较CDKN2A基因在正常人与胰腺癌患者的表达差异,并分析CDKN2A基因CNV与胰腺癌患者预后的关系。应用DIVAD中基因本体分析(GO分析)联合KEGG对CDKN2A和其相关共表达基因进行功能基因富集分析。结果:通过对TCGA数据库挖掘发现,CDKN2A基因CNV与其mRNA表达呈正相关(Pearson:r=0.102,Spearman:r=0.257)。CDKN2A基因CNV胰腺癌中HOXC6、SLC2A1 mRNA表达水平明显升高,GGA2、MTAP mRNA表达水平明显降低(均P<0.05)。相关性研究发现,CDKN2A基因与MTAP mRNA呈明显正相关(Pearson:r=0.42,Spearman:r=0.55)。通过对GTEx数据库分析,发现CDKN2A基因在胰腺癌组织中表达明显高于正常胰腺组织(P<0.05)。携带CDKN2A基因CNV的胰腺癌患者总生存率与无瘤生存率均明显低于不携带该基因CNV的胰腺癌患者(均P<0.05)。通过对包括CDKN2A相关共表达基因功能富集分析发现,这些共表达基因的功能主要集中于细胞周期的信号通路。结论:CDKN2A基因CNV在胰腺癌中是一种不良预后因素,可作为预测胰腺癌预后的指标。

Objective： To investigate the copy number variation （CNV） of cyclin-dependent kinase inhibitor 2A （CDKN2A） gene in pancreatic cancer and its relationship to the prognosis of pancreatic cancer patients.Methods： The CNV and RNA Seq V2 data in the Cancer Genome Atlas （TCGA） were used for analysis of correlation between the CDKN2A gene CNV and its mRNA expression, and the influence of CDKN2A gene CNV on the expressions of other genes. The difference in CDKN2A gene expressions between normal subjects and pancreatic cancer patients was compared and the relation of CDKN2A gene CNV with the prognosis of pancreatic cancer patients was analyzed by using TCGA database and GTEx database. Functional enrichment analysis of CDKN2A and its co-expressed genes was performed by using gene ontology analysis （GO analysis） in DIVAD combined with KEGG. Results： By mining the TCGA database, CDKN2A gene CNV was found to be positively correlated with its mRNA expression （Pearson： r=0.102, Spearman： r=0.257）. The expression levels of HOXC6 and SLC2A1 mRNA were significantly increased, while the expression levels of GGA2 and MTAP mRNA were significantly decreased in pancreatic cancer with CDKN2A gene （all P〈0.05）, and the correlation analysis showed that CDKN2A gene was positively correlated with MTAP mRNA （Pearson： r=0.42, Spearman： r=0.55）. The CDKN2A gene expression in pancreatic cancer tissues was found to be significantly higher than that in normal pancreatic tissues by analyzing the GTEx database （P〈0.05）. The overall survival rate and tumor-flee survival rate of pancreatic cancer patients with CDKN2A gene CNV were significantly reduced compared with those without CDKN2A gene CNV （both P〈0.0S）. Functional enrichment analysis of co-expressed genes related to CDKN2A showed that the functions of these co-expressed genes were mainly concentrated in the signal pathways of cell cycle. Conclusion： CDKN2A gene CNV is an unfavorable prognostic factor for pancreatic cancer and can be used as an indicator for estimating the prognosis of pancreatic cancer.